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Inflammasomes in liver diseases

  • Gyongyi Szabo
    Correspondence
    Corresponding author. Address: University of Massachusetts Medical School, Department of Medicine, LRB215, 364 Plantation Street, Worcester, MA 01605, USA. Tel.: +1 508 856 5275; fax: +1 508 856 4770.
    Affiliations
    Department of Medicine, University of Massachusetts Medical School, Worcester, USA
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  • Timea Csak
    Affiliations
    Department of Medicine, University of Massachusetts Medical School, Worcester, USA
    Search for articles by this author
Open AccessPublished:May 24, 2012DOI:https://doi.org/10.1016/j.jhep.2012.03.035

      Summary

      Inflammation is a common element in the pathogenesis of most chronic liver diseases that lead to fibrosis and cirrhosis. Inflammation is characterized by activation of innate immune cells and production of pro-inflammatory cytokines IL-1α, IL-1β, and TNFα. Inflammasomes are intracellular multiprotein complexes expressed in both parenchymal and non-parenchymal cells of the liver that in response to cellular danger signals activate caspase-1, and release IL-1β and IL-18. The importance of inflammasome activation in various forms of liver diseases in relation to liver damage, steatosis, inflammation and fibrosis is discussed in this review.

      Abbreviations:

      NLR (NOD-like receptor), ASC (apoptosis-associated speck like CARD-domain containing protein), IL (interleukin), IL-1R (interleukin-1 receptor), IL-1Ra (interleukin-1 receptor antagonist), NK (natural killer), IFN (interferon), TLR (toll-like receptor), PAMP (pathogen associated molecular pattern), DAMP (damage associated molecular pattern), NALP1 (NACHT, LRR, and PYD domains-containing protein 1), NALP3 (NACHT, LRR, and PYD domains-containing protein 3/cryoporin), NLRC4 (NLR-family CARD domain containing protein 4), AIM2 (absent in melanoma 2), MDP (muramyl dipeptide), NFκB (Nuclear factor kB), MSU (monosodium urate), ROS (reactive oxygen species), NADPH (nicotinamide adenine dinucleotide phosphate oxidase), ATP (adenosine triphosphate), TXNIP (thioredoxin-interacting protein), RIG-I (retinoic acid-inducible gene-I), APAP (N-acetyl-p-aminophenol), I/R (ischaemia-reperfusion), LPS (lipopolysaccharide), ASH (alcoholic steatohepatitis), NASH (nonalcoholic steatohepatitis), MCD (methionine-choline deficient), HFD (high fat diet), CDAA (choline deficient amino acid defined), TNFα (tumor necrosis factor α), MyD88 (myeloid differentiation factor 88), CCl4 (carbon tetrachloride), HCV (hepatitis C virus), HBV (hepatitis B virus)

      Keywords

      Inflammasomes and their signal transduction pathways

      The term “inflammasome”, introduced by Tschopp and colleagues [
      • Martinon F.
      • Burns K.
      • Tschopp J.
      The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.
      ] refers to large multiprotein complexes that sense intracellular danger signals via NOD-like receptors (NLR) [
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ].
      Figure thumbnail fx2
      Figure thumbnail gr1
      Fig. 1Structure of inflammasome and non-inflammasome NLRs and non-NLR inflammasomes.
      The sensor, NLR, forms a complex with the effector molecule, pro-caspase-1, with or without the contribution of an adapter molecule, such as the apoptosis-associated speck like CARD-domain containing protein (ASC) [
      • Martinon F.
      • Burns K.
      • Tschopp J.
      The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.
      ,
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Ye Z.
      • Ting J.P.
      NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ]. Inflammasome activation leads to auto-activation of the 45 kDa inactive pro-caspase-1 precursor into p20 and p10 subunits that form the active caspase-1 [
      • Martinon F.
      • Burns K.
      • Tschopp J.
      The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.
      ,
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Ye Z.
      • Ting J.P.
      NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ], resulting in the cleavage of pro-IL-1β and pro-IL-18 into mature forms, and inactivation of IL-33 [
      • Martinon F.
      • Burns K.
      • Tschopp J.
      The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.
      ,
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Ye Z.
      • Ting J.P.
      NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ,
      • Cayrol C.
      • Girard J.P.
      The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.
      ]. IL-1β is a pro-inflammatory cytokine, a central regulator of inflammation that binds to the IL-1 receptor (IL-1R) to exert its broad biological effects. IL-1R also recognizes IL-1α and binds IL-1R antagonist (IL-1Ra), the latter inhibiting IL-1R activation [
      • Dinarello C.A.
      Immunological and inflammatory functions of the interleukin-1 family.
      ]. IL-18 activates natural killer (NK) cells to produce IFNγ [
      • Dinarello C.A.
      Immunological and inflammatory functions of the interleukin-1 family.
      ], while IL-33 is a chromatin-associated cytokine of the IL-1 family that drives Th2 responses [
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ,
      • Dinarello C.A.
      Immunological and inflammatory functions of the interleukin-1 family.
      ]. The full-length active IL-33 is cleaved and inactivated by caspase-1 [
      • Cayrol C.
      • Girard J.P.
      The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1.
      ].
      Inflammasome activation is thought to be a two-step process in which signal 1 (mostly from TLR activation) upregulates inflammasome expression and signal 2 triggers functional inflammasome activation by an inflammasome ligand [
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ]. A recent publication suggests that the priming step is required only for activation of NLRP3 and not other inflammasomes such as NLRC4 or AIM2 [
      • Bauernfeind F.
      • Bartok E.
      • Rieger A.
      • Franchi L.
      • Nunez G.
      • Hornung V.
      Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome.
      ]. Inflammasome ligands include both pathogen-associated (PAMPs) and endogenous danger molecules (DAMPs) (summerized in Table 1) [
      • Martinon F.
      • Burns K.
      • Tschopp J.
      The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of pro-IL-beta.
      ,
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Ye Z.
      • Ting J.P.
      NLR, the nucleotide-binding domain leucine-rich repeat containing gene family.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ]. To date, four main prototypes of inflammasomes have been characterized: NLRP1 (NALP1); NLRP3 (NALP3, cryporin); NLRC4 (IPAF) and AIM2 [
      • Martinon F.
      • Mayor A.
      • Tschopp J.
      The inflammasomes: guardians of the body.
      ,
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ]. They have different ligand recognition sites and utilization of adapter molecules but all culminate in caspase-1 activation.
      Table 1Known activators of inflammasome NLRs.

      NLRP1 inflammasome

      NLRP1 (NACHT, LRR, and PYD domains-containing protein 1), the first inflammasome described, can directly interact with caspase-1 through its C-terminal CARD domain, and in humans, the presence of ASC enhances the activity of the complex [
      • Schroder K.
      • Tschopp J.
      The inflammasomes.
      ]. Murine NLRP1 is unable to bind to ASC because it lacks a functional PYD domain [
      • Schroder K.
      • Tschopp J.
      The inflammasomes.
      ]. Multiple alternatively spliced transcript variants of human NLRP1 exist [
      • Pontillo A.
      • Catamo E.
      • Arosio B.
      • Mari D.
      • Crovella S.
      NALP1/NLRP1 genetic variants are associated with Alzheimer disease.
      ].
      Figure thumbnail fx3

      NLRP3 inflammasome

      NLRP3 (NACHT, LRR, and PYD domains-containing protein 3, cryoporin) was first described by Hoffman et al. who discovered four single mutations in the NLRP3 gene, in families with familial cold autoinflammatory syndrome and Muckle–Wells syndrome, which lead to increased IL-1β production [
      • Hoffman H.M.
      • Mueller J.L.
      • Broide D.H.
      • Wanderer A.A.
      • Kolodner R.D.
      Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome.
      ]. Later, Agostini et al. reported that NLRP3 forms an IL-1β-processing inflammasome complex [
      • Agostini L.
      • Martinon F.
      • Burns K.
      • McDermott M.F.
      • Hawkins P.N.
      • Tschopp J.
      NALP3 forms an IL-1β processing inflammasome with increased activity in Muckle–Wells auto-inflammatory disorder.
      ]. To date, NLRP3 is the most fully characterized member of the inflammasome family. It consists of the NOD-like receptor NLRP3, the adaptor molecule ASC, and the effector molecule pro-caspase-1. Since NLRP3 does not contain a CARD domain, the presence of the adaptor molecule is necessary for the complex formation [
      • Schroder K.
      • Tschopp J.
      The inflammasomes.
      ].
      The expression of NLRP3 is tightly regulated at the transcriptional level via NFκB [
      • Bauernfeind F.G.
      • Horvath G.
      • Stutz A.
      • Alnemri E.S.
      • MacDonald K.
      • Speert D.
      • et al.
      Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
      ]. NLRP3 activation requires two signals. Cell priming with an NFκB activator, such as the TLR4-ligand LPS, is the first step of NLRP3 inflammasome activation [
      • Bauernfeind F.G.
      • Horvath G.
      • Stutz A.
      • Alnemri E.S.
      • MacDonald K.
      • Speert D.
      • et al.
      Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
      ] leading to up regulation of NLRP3 expression [
      • Bauernfeind F.G.
      • Horvath G.
      • Stutz A.
      • Alnemri E.S.
      • MacDonald K.
      • Speert D.
      • et al.
      Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
      ] while the second signal includes a broad variety of activators.
      Three major pathways have been implicated in NLRP3 inflammasome activation (Fig. 2) induced by a wide variety of activators [
      • Martinon F.
      • Petrilli V.
      • Mayor A.
      • Tardivel A.
      • Tshopp J.
      Gout-associated uric acid crystals activate the NALP3 inflammasome.
      ,
      • Eisenbarth S.C.
      • Colegio O.R.
      • O‘Connor W.
      • Sutterwala F.S.
      • Flavell R.A.
      Crucial role for the Nalp3 inflammasome in the immunstimulatory properties of aluminium adjuvants.
      ,
      • Hornung V.
      • Bauernfeind F.
      • Halle A.
      • Samstad E.O.
      • Kono H.
      • Rock K.L.
      • et al.
      Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization.
      ,
      • Dostert C.
      • Petrilli V.
      • Van Bruggen R.
      • Steele C.
      • Mossman B.T.
      • Tschopp J.
      Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
      ,
      • Halle A.
      • Hornung V.
      • Petzold G.C.
      • Stewart C.R.
      • Monks B.G.
      • Reinheckel T.
      • et al.
      The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.
      ,
      • Yamasaki K.
      • Muto J.
      • Taylor K.R.
      • Cogen A.L.
      • Audish D.
      • Bertin J.
      • et al.
      NLRP3/cryoporin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.
      ,
      • Dostert C.
      • Guarda G.
      • Romero J.F.
      • Menu P.
      • Gross O.
      • Tardivel A.
      • et al.
      Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
      ,
      • Sharp F.A.
      • Ruane D.
      • Claass B.
      • Creaqh E.
      • Harris J.
      • Malyala P.
      • et al.
      Uptake of particulate vaccine adjuvants by dendritic cells activate the NALP3 inflammasome.
      ,
      • Duewell P.
      • Kono H.
      • Rayner K.J.
      • Sirois C.M.
      • Vladimer G.
      • Bauernfeind F.G.
      • et al.
      NLRP3 inflammasome are required for atherogenesis and activated by cholesterol crystals.
      ,
      • Mariathasan S.
      • Weiss D.S.
      • Newton K.
      • McBride J.
      • O‘Rourke K.
      • Roose-Girma M.
      • et al.
      Cryopyrin activates the inflammasome in response to toxins and ATP.
      ,
      • Gurcel L.
      • Abrami L.
      • Girardin S.
      • Tschopp J.
      • van der Goot F.G.
      Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.
      ,
      • Munoz-Planillo R.
      • Franchi L.
      • Miller L.S.
      • Nunez G.
      A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome.
      ,
      • Harder J.
      • Franchi L.
      • Munoz-Planillo R.
      • Park J.H.
      • Reiner T.
      • Nunez G.
      Activation of Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NFkappa B activation but proceeds independently of TLR signaling and P2X7 receptor.
      ,
      • Ichinohe T.
      • Pang I.K.
      • Iwasaki A.
      Influenza virus activates inflammasomes via its intracellular M2 ion channel.
      ,
      • Kanneganti T.D.
      • Lamkanfi M.
      • Kim Y.G.
      • Chen G.
      • Park J.H.
      • Franchi L.
      • et al.
      Pannexin-1 mediated recognition of bacterial molecules activates the cryoporin inflammasome independent of toll-like receptor signaling.
      ,
      • Kanneganti T.D.
      • Ozören N.
      • Body-Malapel M.
      • Amer A.
      • Park J.H.
      • Franchi L.
      • et al.
      Bacterial RNA and small antiviral compounds activate caspase-1 through cryoporin/Nalp3.
      ]. First, extracellular ATP sensed by the P2X7 purinergic receptor results in potassium efflux and recruitment of pannexin that induces NLRP3 activation [
      • Mariathasan S.
      • Weiss D.S.
      • Newton K.
      • McBride J.
      • O‘Rourke K.
      • Roose-Girma M.
      • et al.
      Cryopyrin activates the inflammasome in response to toxins and ATP.
      ,
      • Kanneganti T.D.
      • Lamkanfi M.
      • Kim Y.G.
      • Chen G.
      • Park J.H.
      • Franchi L.
      • et al.
      Pannexin-1 mediated recognition of bacterial molecules activates the cryoporin inflammasome independent of toll-like receptor signaling.
      ,
      • Petrilli V.
      • Papin S.
      • Dostert C.
      • Mayor A.
      • Martinon F.
      • Tschopp J.
      Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
      ]. Pannexin is a membrane pore that allows the delivery of extracellular PAMPs and DAMPs into the cytosol [
      • Kanneganti T.D.
      • Lamkanfi M.
      • Kim Y.G.
      • Chen G.
      • Park J.H.
      • Franchi L.
      • et al.
      Pannexin-1 mediated recognition of bacterial molecules activates the cryoporin inflammasome independent of toll-like receptor signaling.
      ].
      Second, NLRP3 activation is induced by crystals or large particles such as silica, asbestos, aluminium, amyloid, monosodium urate, and cholesterol [
      • Martinon F.
      • Petrilli V.
      • Mayor A.
      • Tardivel A.
      • Tshopp J.
      Gout-associated uric acid crystals activate the NALP3 inflammasome.
      ,
      • Eisenbarth S.C.
      • Colegio O.R.
      • O‘Connor W.
      • Sutterwala F.S.
      • Flavell R.A.
      Crucial role for the Nalp3 inflammasome in the immunstimulatory properties of aluminium adjuvants.
      ,
      • Hornung V.
      • Bauernfeind F.
      • Halle A.
      • Samstad E.O.
      • Kono H.
      • Rock K.L.
      • et al.
      Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization.
      ,
      • Dostert C.
      • Petrilli V.
      • Van Bruggen R.
      • Steele C.
      • Mossman B.T.
      • Tschopp J.
      Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
      ,
      • Halle A.
      • Hornung V.
      • Petzold G.C.
      • Stewart C.R.
      • Monks B.G.
      • Reinheckel T.
      • et al.
      The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.
      ,
      • Yamasaki K.
      • Muto J.
      • Taylor K.R.
      • Cogen A.L.
      • Audish D.
      • Bertin J.
      • et al.
      NLRP3/cryoporin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.
      ,
      • Dostert C.
      • Guarda G.
      • Romero J.F.
      • Menu P.
      • Gross O.
      • Tardivel A.
      • et al.
      Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
      ,
      • Sharp F.A.
      • Ruane D.
      • Claass B.
      • Creaqh E.
      • Harris J.
      • Malyala P.
      • et al.
      Uptake of particulate vaccine adjuvants by dendritic cells activate the NALP3 inflammasome.
      ,
      • Duewell P.
      • Kono H.
      • Rayner K.J.
      • Sirois C.M.
      • Vladimer G.
      • Bauernfeind F.G.
      • et al.
      NLRP3 inflammasome are required for atherogenesis and activated by cholesterol crystals.
      ]. It has been shown that disruption of lysosomes by chemical damage [
      • Gong Y.N.
      • Wang X.
      • Wang J.
      • Yang Z.
      • Li S.
      • Yang J.
      • et al.
      Chemical probing reveals insights into the signaling mechanism of inflammasome activation.
      ] or lysosomal damage after phagocytosis of these large particles induces NLRP3 inflammasome activation [
      • Hornung V.
      • Bauernfeind F.
      • Halle A.
      • Samstad E.O.
      • Kono H.
      • Rock K.L.
      • et al.
      Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization.
      ,
      • Halle A.
      • Hornung V.
      • Petzold G.C.
      • Stewart C.R.
      • Monks B.G.
      • Reinheckel T.
      • et al.
      The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.
      ,
      • Duewell P.
      • Kono H.
      • Rayner K.J.
      • Sirois C.M.
      • Vladimer G.
      • Bauernfeind F.G.
      • et al.
      NLRP3 inflammasome are required for atherogenesis and activated by cholesterol crystals.
      ]. Consistent with the role of lysosomal damage in inflammasome activation, the role of a lysosomal protease, cathepsin B, has been implicated in certain forms of NLRP3 activation [
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ,
      • Dostert C.
      • Guarda G.
      • Romero J.F.
      • Menu P.
      • Gross O.
      • Tardivel A.
      • et al.
      Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
      ,
      • Tschopp J.
      • Schroder K.
      NLRP3 inflammasome activation: the convergence of multiple signaling pathways on ROS production?.
      ].
      Third, some studies suggest that reactive oxygen species (ROS) contribute to inflammasome activation. This is based on the observation that inhibitors or scavengers that block mitochondrial ROS or NADPH oxidase suppress inflammasome activation [
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ,
      • Dostert C.
      • Petrilli V.
      • Van Bruggen R.
      • Steele C.
      • Mossman B.T.
      • Tschopp J.
      Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
      ,
      • Fubini B.
      • Hubbard A.
      Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis.
      ,
      • Cruz C.M.
      • Rinna A.
      • Forman H.J.
      • Ventura A.L.
      • Persechini P.M.
      • Ojcius D.M.
      ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages.
      ,
      • Zhou R.
      • Tardivel A.
      • Thorens B.
      • Choi I.
      • Tschopp J.
      Thioredoxin-interacting protein links oxidative stress to inflammasome activation.
      ]. ROS induction may represent a common pathway from different cellular insults. For example, large particles [
      • Fubini B.
      • Hubbard A.
      Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis.
      ] and ATP [
      • Cruz C.M.
      • Rinna A.
      • Forman H.J.
      • Ventura A.L.
      • Persechini P.M.
      • Ojcius D.M.
      ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages.
      ], that are known “inflammasome-activators”, induce ROS production. ROS-dependent release of thioredoxin-interacting protein (TXNIP) from thioredoxin and direct interaction between TXNIP and NLRP3 have been described [
      • Zhou R.
      • Tardivel A.
      • Thorens B.
      • Choi I.
      • Tschopp J.
      Thioredoxin-interacting protein links oxidative stress to inflammasome activation.
      ]. However, ROS production does not always result in inflammasome activation [
      • Bauernfeind F.
      • Ablasser A.
      • Bartok E.
      • Kim S.
      • Schmid-Burgk J.
      • Cavlar T.
      • et al.
      Inflammasomes: current understanding and open questions.
      ,
      • Bauernfeind F.
      • Bartok E.
      • Rieger A.
      • Franchi L.
      • Nunez G.
      • Hornung V.
      Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome.
      ,
      • Hornung V.
      • Bauernfeind F.
      • Halle A.
      • Samstad E.O.
      • Kono H.
      • Rock K.L.
      • et al.
      Silica crystals and aluminium salts activate the NALP3 inflammasome through phagosomal destabilization.
      ,
      • Schroder K.
      • Tschopp J.
      The inflammasomes.
      ] and NLRP3 activation is not impaired in macrophages deficient in NADPH oxidase subunits [
      • van Bruggen R.
      • Köker M.Y.
      • Jansen M.
      • van Houdt M.
      • Roos D.
      • Kuijpers T.W.
      • et al.
      Human NLRP3 inflammasome activation is NO1–4 independent.
      ,
      • van de Veerdonk F.L.
      • Smeekens S.P.
      • Joosten L.A.
      • Kullberg B.J.
      • Dinarello C.A.
      • van der Meer J.W.
      • et al.
      Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease.
      ]. In addition Bauernfeind et al. showed that ROS inhibitors blocked priming and not activation of the NLRP3 inflammasome [
      • Bauernfeind F.
      • Bartok E.
      • Rieger A.
      • Franchi L.
      • Nunez G.
      • Hornung V.
      Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome.
      ].

      NLRC4 inflammasome

      NLRC4/IPAF (NLR-family CARD domain containing protein 4) inflammasome is activated by the flagellin of Gram-negative and Gram-positive bacteria [
      • Miao E.A.
      • Mao D.P.
      • Yudkosky N.
      • Bonneau R.
      • Loranq C.G.
      • Warren S.E.
      • et al.
      Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome.
      ,
      • Mariathasan S.
      • Newton K.
      • Monack D.M.
      • Vucic D.
      • French D.M.
      • Lee W.P.
      • et al.
      Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
      ,
      • Vinzing M.
      • Eitel J.
      • Lippmann J.
      • Hocke A.C.
      • Zahlten J.
      • Slevogt H.
      • et al.
      NAIP and Ipaf control Legionella pneumophila replication in human cells.
      ] or the type III secretion system (T3SS) of Gram-negative bacteria [
      • Miao E.A.
      • Mao D.P.
      • Yudkosky N.
      • Bonneau R.
      • Loranq C.G.
      • Warren S.E.
      • et al.
      Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome.
      ,
      • Mariathasan S.
      • Newton K.
      • Monack D.M.
      • Vucic D.
      • French D.M.
      • Lee W.P.
      • et al.
      Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
      ,
      • Vinzing M.
      • Eitel J.
      • Lippmann J.
      • Hocke A.C.
      • Zahlten J.
      • Slevogt H.
      • et al.
      NAIP and Ipaf control Legionella pneumophila replication in human cells.
      ]. The steps of NRLC4 inflammasome activation are not yet fully explored. Zhao et al. have reported that other NLR proteins, such as murine NAIP5 and NAIP2, interact with the bacterial flagellin or type III secretion system (T3SS) rod components, respectively, and promote the assembly and activation of NLRC4 inflammasome [
      • Zhao Y.
      • Yang J.
      • Shi J.
      • Gong Y.N.
      • Lu Q.
      • Xu H.
      • et al.
      The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.
      ]. Human NAIP recognizes the T3SS needle subunit [
      • Zhao Y.
      • Yang J.
      • Shi J.
      • Gong Y.N.
      • Lu Q.
      • Xu H.
      • et al.
      The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.
      ].

      AIM 2 inflammasome

      AIM 2 (absent in melanoma 2) is a cytosolic dsDNA sensing inflammasome [
      • Muruve D.A.
      • Pétrilli V.
      • Zaiss A.K.
      • White L.R.
      • Clark S.A.
      • Ross P.J.
      • et al.
      The inflammasome recognizes cytosolic microbial and host DNA and triggers innate immune response.
      ,
      • Hornung V.
      • Ablasser A.
      • Charrel-Dennis M.
      • Bauernfeind F.
      • Horvath G.
      • Cafrey D.R.
      • et al.
      AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC.
      ,
      • Nakahira K.
      • Haspel J.A.
      • Rathinam V.A.
      • Lee S.J.
      • Dolinay T.
      • Lam H.C.
      • et al.
      Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome.
      ] activated by bacterial, viral, and mammalian host DNA to trigger caspase-1 activation [
      • Muruve D.A.
      • Pétrilli V.
      • Zaiss A.K.
      • White L.R.
      • Clark S.A.
      • Ross P.J.
      • et al.
      The inflammasome recognizes cytosolic microbial and host DNA and triggers innate immune response.
      ,
      • Hornung V.
      • Ablasser A.
      • Charrel-Dennis M.
      • Bauernfeind F.
      • Horvath G.
      • Cafrey D.R.
      • et al.
      AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC.
      ,
      • Nakahira K.
      • Haspel J.A.
      • Rathinam V.A.
      • Lee S.J.
      • Dolinay T.
      • Lam H.C.
      • et al.
      Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome.
      ]. AIM2 can directly bind to its ligand [
      • Hornung V.
      • Ablasser A.
      • Charrel-Dennis M.
      • Bauernfeind F.
      • Horvath G.
      • Cafrey D.R.
      • et al.
      AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC.
      ] and may contribute to the pathogenesis of autoimmune diseases by recognizing the mammalian DNA [
      • Rathinam V.A.K.
      • Jiang Z.
      • Waggoner S.N.
      • Sharma S.
      • Cole L.E.
      • Waggoner L.
      • et al.
      The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.
      ]. Caspase-1 activation can also occur as a result of inflammasome activation by dsRNA via the helicase receptor RIG-I, after association with the inflammasome adaptor molecule ASC [
      • Poeck H.
      • Bscheider M.
      • Gross O.
      • Finger K.
      • Roth S.
      • Rebsamen M.
      • et al.
      Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin-1β production.
      ].

      Secretion of interleukin-1β

      Activation of inflammasomes culminates in caspase-1 activation and IL-1β secretion. Early observations suggested that IL-1β was secreted independently of the “classical” endoplasmatic reticulum-Golgi route [
      • Rubartelli A.
      • Cozzolino F.
      • Talio M.
      • Sitia R.
      A novel secretory pathway for interleukin-1β, a protein lacking a signal sequence.
      ]. The molecular mechanisms of IL-1β secretion are yet to be clarified. Some studies suggested that caspase-1 was present in secretory lysosomes together with other lysosomal proteins and pro-IL-1β [
      • Andrei C.
      • Margiocco P.
      • Poggi A.
      • Lotti L.V.
      • Torrisi M.R.
      • Rubartelli A.
      Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: implications for inflammatory processes.
      ]. Andrei et al. reported that ATP-triggered potassium efflux led to calcium-dependent phospholipase C activation, followed by activation of phospholipase A2 and eventually exocytosis and IL-1β release [
      • Andrei C.
      • Margiocco P.
      • Poggi A.
      • Lotti L.V.
      • Torrisi M.R.
      • Rubartelli A.
      Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: implications for inflammatory processes.
      ]. Recently, pyroptosis has been suggested as an alternative mechanism for IL-1β release [
      • Dinarello C.A.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      ].
      Importantly, IL-1 production has an auto-regulatory loop. The secreted active IL-1β or IL-1α can activate the IL-1 receptor complex and increase the transcription of its own precursor as well as the synthesis of the inflammasome components [
      • Dinarello C.A.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      ,
      • Dinarello C.A.
      • Ikejima T.
      • Warner S.J.
      • et al.
      Interleukin 1 induces interleukin 1. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro.
      ,
      • Goldbach-Mansky R.
      • Dailey N.J.
      • Cann S.W.
      • Gelabert A.
      • Jones J.
      • Rubin B.I.
      • et al.
      Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition.
      ,
      • Bauernfeind F.G.
      • Horvath G.
      • Stutz A.
      • Alnemri E.S.
      • MacDonald K.
      • Speert D.
      • et al.
      Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
      ]. This amplification loop suggests that small amounts of IL-1β could have a significant biological effect.

      Inflammasomes regulate cell fate

      Increasing evidence suggests important, IL-1β- and IL-18-independent, “non-canonical” roles of inflammasomes that have been recently reviewed by Lamkanfi [
      • Lamkanfi M.
      Emerging inflammasome effector mechanisms.
      ]. In addition to inflammation, inflammasome activation regulates cell death [
      • Lamkanfi M.
      Emerging inflammasome effector mechanisms.
      ,
      • Ting J.P.Y.
      • Willingham S.B.
      • Bergstralh D.T.
      NLRs at the intersection of cell death and immunity.
      ]. NLRP1, NLRC4 (IPAF), and NAIP activate pyroptosis, while NLRP3 activation contributes to pyronecrosis [
      • Ting J.P.Y.
      • Willingham S.B.
      • Bergstralh D.T.
      NLRs at the intersection of cell death and immunity.
      ]. Pyroptosis is a caspase-1-dependent cell death showing similarities to apoptosis and DNA damage. Unlike apoptosis, pyroptosis does not depend on apoptotic caspases and it is accompanied by loss of plasma membrane integrity and lack of chromatin condensation [
      • Ting J.P.Y.
      • Willingham S.B.
      • Bergstralh D.T.
      NLRs at the intersection of cell death and immunity.
      ]. Pyronecrosis shows similarities to necrosis since it is not caspase dependent and leads to breakdown of the plasma membrane without chromatin condensation. NLRP3-induced pyronecrosis utilizes the adaptor molecule ASC, and involves the lysosomal enzyme cathepsin B [
      • Ting J.P.Y.
      • Willingham S.B.
      • Bergstralh D.T.
      NLRs at the intersection of cell death and immunity.
      ]. The loss of plasma membrane integrity might lead to the secretion of various dangerous molecules. Both pyroptosis and pyronecrosis elicit inflammation thereby linking various forms of cell death to innate immune activation. Most recently, Motani et al. have described an ASC-dependent necrosis that is independent of the catalytic activity of caspase-1, but is still inhibited by long-term caspase-1 knockdown [
      • Motani K.
      • Kushiyama H.
      • Imamura R.
      • Kinoshita T.
      • Nishiuchi T.
      • Suda T.
      Caspase-1 protein induces apoptosis-associated speck-like protein caspase-recruitment domain (ASC)-mediated necrosis independently of its catalytic activity.
      ]. Interestingly, a study in HeLa and Chinese hamster ovary (CHO) cells suggests that inflammasome activation and caspase-1 may promote cell survival via sterol regulatory element binding proteins (SREBPs) and lead to membrane repair and healing [
      • Gurcel L.
      • Abrami L.
      • Girardin S.
      • Tschopp J.
      • van der Goot F.G.
      Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.
      ].

      Inflammasomes and interleukin-1β in autoinflammatory diseases

      Figure thumbnail fx4

      Cell-specific expression of inflammasomes in the liver

      Figure thumbnail fx5
      The liver is comprised of both parenchymal (hepatocytes) and immune cells (macrophages, neutrophil leukocytes, dendritic cells, T cells, NK/NKT cells, B lymphocytes), where hepatocytes represent the majority of the cell populations. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, express inflammasomes and there is increasing evidence that inflammasomes exist and are functionally active in non-immune cells, including hepatocytes [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ,
      • Burdette D.
      • Haskett A.
      • Presser L.
      • McRae S.
      • Iqbal J.
      • Waris G.
      Hepatitis C virus activates interleukin-1 {beta} via caspase-1-inflammasome complex.
      ,
      • Yan W.
      • Chang Y.
      • Liang X.
      • Cardinal J.S.
      • Huang H.
      • Thorne S.H.
      • et al.
      High mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases.
      ], stellate cells [
      • Watanabe A.
      • Sohail M.A.
      • Gomes D.A.
      • Hashmi A.
      • Nagata J.
      • Sutterwala F.S.
      • et al.
      Inflammasome-mediated regulation of hepatic stellate cells.
      ], endothelial cells [
      • Kolly L.
      • Busso N.
      • Palmer G.
      • Talabot-Ayer D.
      • Chobaz V.
      • So A.
      Expression and function of NALP3 inflammasome in rheumatoid synovium.
      ,
      • Imaeda A.B.
      • Watanabe A.
      • Sohail M.A.
      • Mahmood S.
      • Mohamadnejad M.
      • Sutterwala F.S.
      • et al.
      Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.
      ], and myofibroblasts [
      • Rawat R.
      • Cohen T.V.
      • Ampong B.
      • Francia D.
      • Henriques-Pons A.
      • Hoffman E.P.
      • et al.
      Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle.
      ]. Hepatocytes, bile duct epithelial cells and stellate cells express ASC protein [
      • Kummer J.A.
      • Broekhuizen R.
      • Everett H.
      • Agostini L.
      • Kuijk L.
      • Martinon F.
      • et al.
      Inflammasome components NALP1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response.
      ,
      • Watanabe A.
      • Sohail M.A.
      • Gomes D.A.
      • Hashmi A.
      • Nagata J.
      • Sutterwala F.S.
      • et al.
      Inflammasome-mediated regulation of hepatic stellate cells.
      ,
      • Masumoto J.
      • Taniguchi S.
      • Nakayama J.
      • Shihara M.
      • Hidaka E.
      • Katsuyama T.
      • et al.
      Expression of apoptosis associated speck-like protein containing a caspase-recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues.
      ]. The liver resident macrophages, Kupffer cells, produce significant amounts of IL-1β [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ] and express most of the NLRs (Petrasek and Szabo, unpublished data), although NLRP1 expression was absent in one study [
      • Kummer J.A.
      • Broekhuizen R.
      • Everett H.
      • Agostini L.
      • Kuijk L.
      • Martinon F.
      • et al.
      Inflammasome components NALP1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response.
      ]. The presence of NLRP3 inflammasome and/or inflammasome activation has been shown in sinusoidal endothelial cells [
      • Imaeda A.B.
      • Watanabe A.
      • Sohail M.A.
      • Mahmood S.
      • Mohamadnejad M.
      • Sutterwala F.S.
      • et al.
      Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.
      ], stellate cells [
      • Watanabe A.
      • Sohail M.A.
      • Gomes D.A.
      • Hashmi A.
      • Nagata J.
      • Sutterwala F.S.
      • et al.
      Inflammasome-mediated regulation of hepatic stellate cells.
      ], and hepatocytes [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ,
      • Burdette D.
      • Haskett A.
      • Presser L.
      • McRae S.
      • Iqbal J.
      • Waris G.
      Hepatitis C virus activates interleukin-1 {beta} via caspase-1-inflammasome complex.
      ,
      • Yan W.
      • Chang Y.
      • Liang X.
      • Cardinal J.S.
      • Huang H.
      • Thorne S.H.
      • et al.
      High mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases.
      ,
      • Shimizu S.
      • Eguchi Y.
      • Kamiike W.
      • Akao Y.
      • Kosaka H.
      • Hasegawa J.
      • et al.
      Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes.
      ]. The cell-specific expression of the inflammasome components in the liver is summarized in Fig. 3.
      Figure thumbnail gr3
      Fig. 3Cell-specific inflammasome expression in the liver.

      The role of inflammasomes in liver diseases

      The below detailed potential triggers of inflammasomes in liver diseases are summarized in Fig. 4.

      Ischemia–reperfusion

      Ischemia–reperfusion (I/R) has clinical relevance to liver transplantation, partial hepatectomy, and hypovolemic shock [
      • Abu-Amara M.
      • Yang S.Y.
      • Tapuira N.
      • Fuller B.
      • Davidson B.
      • Seifalian A.
      Liver ischemia/reperfusion injury: processes in inflammatory networks—review.
      ]. The characteristics of I/R are hepatocyte death, release of DAMPs, inflammatory cell infiltration, Kupffer cell activation, ROS production, and disruption of liver sinusoidal endothelial cells (LSEC) that can all lead to inflammasome activation [
      • Jaeschke H.
      Reactive oxygen and mechanisms of inflammatory liver injury: present concepts.
      ]. Silencing NLRP3 ameliorated I/R-induced hepatocellular injury and reduced IL-1β, IL-18, HMGB1, IL-6, and TNFα release via inhibition of caspase-1 and NFκB activity [
      • Zhu P.
      • Duan L.
      • Chen J.
      • Xiong A.
      • Xu Q.
      • Zhang H.
      • et al.
      Gene silencing of NALP3 protects against liver ishaemia-reperfusion injury in mice.
      ]. Consistent with this, decreased caspase-1 activation was found in the presence of the antioxidant N-acetylcysteine, in I/R injury [
      • Shimizu S.
      • Eguchi Y.
      • Kamiike W.
      • Akao Y.
      • Kosaka H.
      • Hasegawa J.
      • et al.
      Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes.
      ].
      Involvement of caspase-1 (ICE) and apoptosis were observed during the re-oxygenation phase in contrast to the predominantly necrotic features in the hypoxic phase [
      • Shimizu S.
      • Eguchi Y.
      • Kamiike W.
      • Akao Y.
      • Kosaka H.
      • Hasegawa J.
      • et al.
      Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes.
      ]. Caspase-1 activation was present during hypoxia and during the re-oxygenation phase, and a specific caspase-1 inhibitor (YVAD) prevented I/R-induced cell death [
      • Shimizu S.
      • Eguchi Y.
      • Kamiike W.
      • Akao Y.
      • Kosaka H.
      • Hasegawa J.
      • et al.
      Involvement of ICE family proteases in apoptosis induced by reoxygenation of hypoxic hepatocytes.
      ]. The role of the inflammasome/caspase-1 system in I/R injury is further supported by observations where IL-1R antagonist pretreatment, delivery of an IL-1 receptor antagonist (IL-1Ra) cDNA into the liver, or IL-18 neutralizing antibodies significantly reduced liver damage, inflammation, and mortality in animal models [
      • Shito M.
      • Wakabayashi G.
      • Masakazu U.
      • Motohide S.
      • Nozomu S.
      • Masao E.
      • et al.
      Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ishaemia-reperfusion in the rat.
      ,
      • Harada H.
      • Wakabayashi G.
      • Takayanagi A.
      • Shimazu M.
      • Matsumotot K.
      • Obara H.
      • et al.
      Transfer of the interleukin-1 receptor antagonist gene into rat liver abrogates hepatic ischemia-reperfusion injury.
      ,
      • Takeuchi D.
      • Yoshidome H.
      • Kato A.
      • Ito H.
      • Kimura F.
      • Shimizu H.
      • et al.
      Interleukin 18 causes hepatic ischamia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice.
      ]. Notably, TLR4 and TLR9, both of which control IL-1β and NLRP transcription, play a role in I/R liver injury [
      • Tsung A.
      • Hoffman R.A.
      • Izuishi K.
      • Critchlow N.D.
      • Nakao A.
      • Chan M.H.
      • et al.
      Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.
      ,
      • Bamboat Z.M.
      • Balachandran V.P.
      • Ocuin L.M.
      • Obaid H.
      • Plitas G.
      • DeMatteo R.P.
      Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury.
      ].
      Recent findings suggested that caspase-1 was hepatoprotective in a trauma model [
      • Menzel C.L.
      • Sun Q.
      • Loughran P.A.
      • Pape H.C.
      • Billiar T.R.
      • Scott M.J.
      Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation.
      ]; however, NLRP3-independent caspase-1 activation was found in hemorrhagic shock and trauma in I/R injury.

      Endotoxin-induced liver injury and cholestasis

      Endotoxin (lipopolysaccharide (LPS)), a cell wall component of Gram-negative bacteria, is a major mediator of sepsis-induced liver damage, multi-organ failure, and chronic liver disease. Owing to the portal blood supply arriving from the intestines and its unique microcirculation, the liver is exposed to high concentrations of nutrients and gut-derived substances including LPS. The role of the gut microbiota, increased intestinal permeability and portal endotoxinaemia has been described in several liver diseases [
      • Szabo G.
      • Bala S.
      • Petrasek J.
      • Gattu A.
      Gut-liver axis and sensing microbes.
      ].
      LPS, a ligand of TLR4, is a potent inducer of mRNA expression of all inflammasome components (NLRP3, ASC, caspase-1 and pannexin-1), pro-IL-1β and pro-IL-18 via NFκB activation [
      • Bauernfeind F.G.
      • Horvath G.
      • Stutz A.
      • Alnemri E.S.
      • MacDonald K.
      • Speert D.
      • et al.
      Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
      ,
      • Ganz M.
      • Csak T.
      • Nath B.
      • Szabo G.
      LPS stimulation induces and activates the Nalp3 inflammasome in the liver.
      ], although TLR-independent, LPS-induced upregulation of inflammasome has also been described [
      • Kanneganti T.D.
      • Lamkanfi M.
      • Kim Y.G.
      • Chen G.
      • Park J.H.
      • Franchi L.
      • et al.
      Pannexin-1 mediated recognition of bacterial molecules activates the cryoporin inflammasome independent of toll-like receptor signaling.
      ]. In mice, in vivo LPS administration increased the mRNA expression of the components of the inflammasome as well as serum and liver mature IL-1β levels, indicating caspase-1/inflammasome activation [
      • Ganz M.
      • Csak T.
      • Nath B.
      • Szabo G.
      LPS stimulation induces and activates the Nalp3 inflammasome in the liver.
      ].
      Priming with heat-killed Proprionibacterium acnes induced liver inflammatory cell aggregates and rendered mice susceptible to LPS-induced liver injury [
      • Mizoguchi Y.
      • Tsutsui H.
      • Miyajima K.
      • Sakagami Y.
      • Seki S.
      • Kobayashi K.
      • et al.
      The protective effects of prostaglandin E1 in an experimental massive hepatic cell necrosis model.
      ,
      • Romics Jr, L.
      • Dolganiuc A.
      • Kodys K.
      • Drechsler Y.
      • Oak A.
      • Velayudham A.
      • et al.
      Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up-regulation of MD-2 in mice.
      ]. IL-18 and IL-1β played a role in this process [
      • Okamura H.
      • Tsutsi H.
      • Komatsu T.
      • Yutsudo M.
      • Hakura A.
      • Tanimoto T.
      • et al.
      Cloning of a new cytokine that induces IFN-gamma production by T cells.
      ,
      • Gu Y.
      • Kuida K.
      • Tsutsui H.
      • Ku G.
      • Hsiao K.
      • Fleming M.A.
      • et al.
      Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.
      ,
      • Matsui K.
      • Yoshimoto T.
      • Tsutsui H.
      • Hyodo Y.
      • Hayashi N.
      • Hiroishi K.
      • et al.
      Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.
      ,
      • Sakao Y.
      • Takeda K.
      • Tsutsui H.
      • Kaisho T.
      • Nomura F.
      • Okamura H.
      • et al.
      IL-18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock.
      ,
      • Nishioji K.
      • Okanoue T.
      • Mori T.
      • Sakamoto S.
      • Itoh Y.
      Experimental liver injury induced by propionibacterium acnes and lipopolysaccharide in macrophage colony stimulating factor-deficient osteopetrotic (op/op) mice.
      ,
      • Seki E.
      • Tsutsui H.
      • Nakano H.
      • Tsuji N.
      • Hoshino K.
      • Adachi O.
      • et al.
      Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta.
      ,
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ,
      • Calkins C.M.
      • Bensard D.D.
      • Shames B.D.
      • Pulido E.J.
      • Abraham E.
      • Fernandez N.
      • et al.
      IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia.
      ] and Kupffer cell depletion could attenuate the P. acnes/LPS-induced liver injury [
      • Matsui K.
      • Yoshimoto T.
      • Tsutsui H.
      • Hyodo Y.
      • Hayashi N.
      • Hiroishi K.
      • et al.
      Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.
      ,
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ]. In this model, LPS challenge resulted in NLRP3-mediated caspase-1 activation in Kupffer cells in a TRIF-dependent manner without affecting the ATP/P2X7R pathway [
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ]. In TRIF KO mice, hepatic granulomas, but no IL-18 release or liver injury, were present. MyD88, the common TLR adaptor, was crucial for the transcriptional regulation of IL-18 and IL-1β, but not for their maturation and release [
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ]. NLRP3- and ASC-deficient mice were also resistant to P. acnes and LPS-induced liver injury and failed to secrete IL-18 [
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ]. The effector role of IL-1/IL-1R signaling in LPS-induced liver injury was suggested by the observation that IL-1Ra pretreatment attenuated the liver injury [
      • Calkins C.M.
      • Bensard D.D.
      • Shames B.D.
      • Pulido E.J.
      • Abraham E.
      • Fernandez N.
      • et al.
      IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia.
      ].
      Kupffer cells were identified as the main source of LPS-induced IL-1β and IL-18 [
      • Matsui K.
      • Yoshimoto T.
      • Tsutsui H.
      • Hyodo Y.
      • Hayashi N.
      • Hiroishi K.
      • et al.
      Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.
      ,
      • Imamura M.
      • Tsutsui H.
      • Yasuda K.
      • Uchiyama R.
      • Yumikura-Futatsugi S.
      • Mitani K.
      • et al.
      Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice.
      ], and caspase-1-deficient Kupffer cells were not able to secrete mature IL-1β or IL-18 upon LPS stimulation [
      • Seki E.
      • Tsutsui H.
      • Nakano H.
      • Tsuji N.
      • Hoshino K.
      • Adachi O.
      • et al.
      Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta.
      ]. A potential role for other cell types cannot be excluded because in one study depletion of macrophages resulted in only moderate amelioration of the liver injury and it did not influence IL-18 levels [
      • Nishioka T.
      • Kuroishi T.
      • Sugawara Y.
      • Yu Z.
      • Sasano T.
      • Endo Y.
      • et al.
      Induction of serum IL-18 with propionibacterium acnes and lipopolysaccharide in phagocytic macrophage-inactivated mice.
      ].

      Alcoholic and non-alcoholic fatty liver diseases

      There is increasing evidence that gut microbiota, increased gut permeability and endotoxin contribute to the pathogenesis of both alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) [
      • Szabo G.
      • Bala S.
      • Petrasek J.
      • Gattu A.
      Gut-liver axis and sensing microbes.
      ]. In alcoholics with liver disease, as well as in animal models of alcohol-induced liver disease, serum levels of IL-1β were increased [
      • McClain C.J.
      • Cohen D.A.
      • Dinarello C.A.
      • Cannon J.G.
      • Shedlofsky S.I.
      • Kaplan A.M.
      Serum interleukin-1 (IL-1) activity in alcoholic hepatitis.
      ,
      • Valles S.L.
      • Blanco A.M.
      • Azorin I.
      • Guasch R.
      • Pascual M.
      • Gomez-Lechon M.J.
      • et al.
      Chronic ethanol consumption enhances interleukin-1-mediated signal transduction in rat liver and in cultured hepatocytes.
      ]. Hsiang et al. showed IL-1β and TNFα secretion from HepG2 hepatocytes treated with acetaldehyde, a metabolic product of alcohol [
      • Hsiang C.Y.
      • Wu S.L.
      • Cheng S.E.
      • Ho Ty.
      Acetaldehyde-induced interleukin-1beta and tumor necrosis factor-alpha production is inhibited by berberine through nuclear factor-kappaB signaling pathway in HepG2 cells.
      ]. In a mouse model of chronic alcohol feeding, we found increased serum and liver mature IL-1β (17 kDa) levels, increased caspase-1 activation and upregulation of the inflammasome components, NLRP3, ASC, and pro-caspase-1 in the liver (Petrasek and Szabo, manuscript under review) suggesting that inflammasome activation is a component of the liver pathophysiology in ALD.
      The role of inflammasomes and IL-1β in the metabolic syndrome and NASH is receiving increasing attention [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ,
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ,
      • Witek R.P.
      • Stone W.C.
      • Karaca F.G.
      • Syn W.K.
      • Pereirea T.A.
      • Agboola K.M.
      • et al.
      Pan-Caspase inhibitor VX-166 reduces firbosis in an animal model of nonalcoholic steatoehaptitis.
      ,
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • et al.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ,
      • Kamari Y.
      • Shaish A.
      • Vax E.
      • Shemesh S.
      • Kandel-Kfir M.
      • Arbel Y.
      • et al.
      Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
      ,
      • Wen H.
      • Gris D.
      • Lei Y.
      • Jha S.
      • Zhang L.
      • Huang M.T.
      • et al.
      Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
      ,
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ,
      • deRoos B.
      • Rungapamestry V.
      • Ross K.
      • Rucklidge R.
      • Reid M.
      • Duncan G.
      • et al.
      Attenuation of inflammation and cellular-stress related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knock-out mice on a high fat diet.
      ,
      • Isoda K.
      • Sawada S.
      • Ayaori M.
      • Matsuki T.
      • Horai R.
      • Kagata Y.
      • et al.
      Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice.
      ]. IL-1β protein and mRNA levels are increased in various diet-induced NASH models in mice, including methionine–choline-deficient (MCD), high fat (HF) and choline-deficient amino acid-defined (CDAA) diets [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ,
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ,
      • Witek R.P.
      • Stone W.C.
      • Karaca F.G.
      • Syn W.K.
      • Pereirea T.A.
      • Agboola K.M.
      • et al.
      Pan-Caspase inhibitor VX-166 reduces firbosis in an animal model of nonalcoholic steatoehaptitis.
      ,
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • et al.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ,
      • Kamari Y.
      • Shaish A.
      • Vax E.
      • Shemesh S.
      • Kandel-Kfir M.
      • Arbel Y.
      • et al.
      Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
      ,
      • Wen H.
      • Gris D.
      • Lei Y.
      • Jha S.
      • Zhang L.
      • Huang M.T.
      • et al.
      Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
      ,
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ,
      • deRoos B.
      • Rungapamestry V.
      • Ross K.
      • Rucklidge R.
      • Reid M.
      • Duncan G.
      • et al.
      Attenuation of inflammation and cellular-stress related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knock-out mice on a high fat diet.
      ,
      • Isoda K.
      • Sawada S.
      • Ayaori M.
      • Matsuki T.
      • Horai R.
      • Kagata Y.
      • et al.
      Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice.
      ]. Inflammasome activation was associated with steatohepatitis (NASH) [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ,
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • et al.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ] but not with steatosis alone as it occurs in leptin-deficient mice or after short-term high fat diet feeding [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ]. IL-1R KO mice showed attenuated liver injury, steatosis, and fibrosis in the CDAA and HF diet-models [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ,
      • deRoos B.
      • Rungapamestry V.
      • Ross K.
      • Rucklidge R.
      • Reid M.
      • Duncan G.
      • et al.
      Attenuation of inflammation and cellular-stress related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knock-out mice on a high fat diet.
      ]. IL-1β KO mice also had attenuated hepatocellular damage, steatosis, and fibrosis in atherogenic diet-induced steatohepatitis [
      • Kamari Y.
      • Shaish A.
      • Vax E.
      • Shemesh S.
      • Kandel-Kfir M.
      • Arbel Y.
      • et al.
      Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
      ]. IL-1α may also contribute to the pathogenesis of NASH as IL-1α KO mice also showed attenuated liver damage and fibrosis in a HF diet-induced steatohepatitis model [
      • Kamari Y.
      • Shaish A.
      • Vax E.
      • Shemesh S.
      • Kandel-Kfir M.
      • Arbel Y.
      • et al.
      Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
      ]. IL-1R antagonist (IL-1Ra)-deficient mice showed severe hepatic fat accumulation and fibrosis when kept on an atherogenic diet as compared to wild type controls [
      • Isoda K.
      • Sawada S.
      • Ayaori M.
      • Matsuki T.
      • Horai R.
      • Kagata Y.
      • et al.
      Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice.
      ]. Consistent with inflammasome involvement, long-term high fat diet administration resulted in reduced hepatic steatosis in NLRP3 KO mice [
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • et al.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ]. In db/db mice fed an MCD diet, administration of a pan-caspase inhibitor, VX-166, prevented mature IL-1β production and reduced steatosis and fibrosis without preventing liver injury [
      • Witek R.P.
      • Stone W.C.
      • Karaca F.G.
      • Syn W.K.
      • Pereirea T.A.
      • Agboola K.M.
      • et al.
      Pan-Caspase inhibitor VX-166 reduces firbosis in an animal model of nonalcoholic steatoehaptitis.
      ].
      Potential molecular triggers for inflammasome activation in NASH include DAMPs such as DNA, saturated fatty acids, and PAMPs (LPS). In primary hepatocytes, saturated, but not unsaturated fatty acids induce caspase-1 activation and IL-1β release in the presence of LPS [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ]. Furthermore, we have recently demonstrated that danger signals from fatty acid-treated hepatocytes can induce inflammasome activation in liver mononuclear cells [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ], suggesting a crosstalk between liver parenchymal cells and immune cells in NASH (Fig. 4) This intercellular crosstalk provides potential amplification of inflammasome activation and inflammatory pathways in NASH. Observations from MyD88 KO and TLR9 KO mice, where steatohepatitis was attenuated in a CDAA-diet model, lead to the hypothesis that apoptotic DNA from damaged cells is sensed by TLR9 that triggers IL-1β mRNA transcription, while other DAMPs activate the inflammasome [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ]. Fatty acid-induced inflammasome activation in macrophages was NLRP3-dependent and involved increased mitochondrial ROS production and decreased autophagy due to reduced AMPK activity [
      • Wen H.
      • Gris D.
      • Lei Y.
      • Jha S.
      • Zhang L.
      • Huang M.T.
      • et al.
      Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.
      ]. The role of ceramide was also reported in fatty acid-induced inflammasome activation [
      • Vandanmagsar B.
      • Youm Y.H.
      • Ravussin A.
      • Galgani J.E.
      • Stadler K.
      • Mynatt R.L.
      • et al.
      The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
      ].
      Figure thumbnail gr4
      Fig. 4Triggers of inflammasome activation in liver diseases.
      IL-1β promoted the development of hepatic steatosis via suppression of peroxisome proliferator-activated receptor α (PPARα) activity [
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ] but it also increased cell death in lipid-loaded hepatocytes [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ]. Petrasek et al. found that IL-1β increased the hepatotoxic effect of TNFα [
      • Petrasek J.
      • Dolganiuc A.
      • Csak T.
      • Kurt-Jones E.A.
      • Szabo G.
      Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice.
      ]. Thus, the crosstalk between TLR and inflammasome activation is another important determinant of steatohepatitis and the inflammatory response in the liver.
      Understanding the cell-specificity of inflammasome activation in fatty liver disease has implications for future potential therapeutic approaches. An important role for Kupffer cells is supported by the fact that these cells exhibited the highest levels of IL-1β mRNA among liver cell types, and depletion of Kupffer cells markedly decreased liver mRNA and serum IL-1β levels [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ,
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ]. Selective deficiency in IL-1β or IL-1α in liver parenchymal cells, but not in bone-marrow-derived cells, protected mice from diet-induced steatohepatitis and fibrosis [
      • Kamari Y.
      • Shaish A.
      • Vax E.
      • Shemesh S.
      • Kandel-Kfir M.
      • Arbel Y.
      • et al.
      Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
      ]. These observations suggest that inflammasome and IL-1β production by different cell types contribute to different aspects of steatohepatitis.
      Translation of findings from animal models to human NASH has limitations. Increased mRNA expression of NLRP3 inflammasome components was found in human livers of NASH patients [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ] as well as in abdominal fat of obese patients with type 2 diabetes [
      • deRoos B.
      • Rungapamestry V.
      • Ross K.
      • Rucklidge R.
      • Reid M.
      • Duncan G.
      • et al.
      Attenuation of inflammation and cellular-stress related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knock-out mice on a high fat diet.
      ] where NLRP3 levels were decreased after weight loss [
      • deRoos B.
      • Rungapamestry V.
      • Ross K.
      • Rucklidge R.
      • Reid M.
      • Duncan G.
      • et al.
      Attenuation of inflammation and cellular-stress related pathways maintains insulin sensitivity in obese type I interleukin-1 receptor knock-out mice on a high fat diet.
      ]. Interestingly, others found that while weight loss did not influence liver and adipose tissue NLRP3 expression, the hepatic IL-1β, IL-18, and IL-Ra levels were significantly reduced [
      • Moschen A.R.
      • Molnar C.
      • Enrich B.
      • Geiger S.
      • Ebenbichler C.F.
      • Tilg H.
      Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss.
      ]. The lack of an animal model that mimics all features of human NASH challenges translation of specific findings from animals to humans. For example, MyD88 deficiency prevented CDAA-induced NASH in one study and [
      • Miura K.
      • Kodama Y.
      • Inokuchi S.
      • Schnabl B.
      • Aoyama T.
      • Ohnishi H.
      • et al.
      Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice.
      ] it worsened the HF diet-induced steatohepatitis in another study [
      • Hosoi T.
      • Yokoyama S.
      • Matsuo S.
      • Akira S.
      • Ozawa K.
      Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice.
      ]. Further studies are needed to provide clarifications.

      Viral hepatitis

      IL-1β levels are increased in patients with chronic HCV infection and these levels are even higher in those with cryoglobulinaemia [
      • Lapinski T.W.
      The concentration of sFasL, ICE and IL-1beta in the serum and the liver tissue of chronic HCV infected patients.
      ,
      • Antonelli A.
      • Ferri C.
      • Ferrari S.M.
      • Ghiri E.
      • Goglia F.
      • Pampana A.
      • et al.
      Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia.
      ,
      • Antonelli A.
      • Ferri C.
      • Ferrari S.M.
      • DeMarco S.
      • Di Domenicantonio A.
      • Centanni M.
      • et al.
      Interleukin-1β, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis.
      ]. Serum IL-1β and caspase-1 levels are decreased in those individuals who respond to anti-HCV therapy [
      • Lapinski T.W.
      The concentration of sFasL, ICE and IL-1beta in the serum and the liver tissue of chronic HCV infected patients.
      ]. The cellular source of IL-1β in HCV infection is yet to be determined. Kupffer cells have been described as a source of IL-1β because HCV proteins induced IL-1β, TNFα, and IL-10 production from KCs [
      • Antonelli A.
      • Ferri C.
      • Ferrari S.M.
      • DeMarco S.
      • Di Domenicantonio A.
      • Centanni M.
      • et al.
      Interleukin-1β, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis.
      ,
      • Tu Z.
      • Pierce R.H.
      • Kurtis J.
      • Kuroki Y.
      • Crispe I.N.
      • Orloff M.S.
      Hepatitis C virus core protein subverts the antiviral activities of human Kupffer cells.
      ]. Recently, Burdette et al. have reported NLRP3 inflammasome activation and IL-1β production from HCV infected human hepatoma cells (JFH1) [
      • Burdette D.
      • Haskett A.
      • Presser L.
      • McRae S.
      • Iqbal J.
      • Waris G.
      Hepatitis C virus activates interleukin-1 {beta} via caspase-1-inflammasome complex.
      ]. Notably, HCV core protein downregulated caspase-1 and caspase-4 in human B lymphocytes [
      • Wu C.G.
      • Budhu A.
      • Chen S.
      • Zhou X.
      • Popescu N.C.
      • Valerie K.
      • et al.
      Effect of hepatitis C virus core protein on the molecular profiling of human B lymphocytes.
      ]. We found increased expression of NLRP3 inflammasome at the mRNA level in livers of patients with chronic hepatitis C infection suggesting that inflammasome upregulation may be a component of HCV immunopathology [
      • Csak T.
      • Ganz M.
      • Pespisa J.
      • Kodys K.
      • Dolganiuc A.
      • Szabo G.
      Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.
      ].
      Hepatitis B virus (HBV) core antigen induced caspase-1-dependent IL-18 secretion from human PBMCs and IL-18 levels were increased in PBMCs from HBeAg negative patients, suggesting the possibility of inflammasome activation in chronic HBV infection [
      • Manigold T.
      • Böcker U.
      • Chen J.
      • Gundt J.
      • Traber P.
      • Singer M.V.
      • et al.
      Hepatitis B core antigen is a potent inductor of interleukin-18 in peripheral blood mononuclear cells of healthy controls and patients with hepatitis B infection.
      ]. Inflammasome involvement in other viral diseases [
      • Kanneganti T.D.
      Central roles of NLRs and inflammasomes in viral infection.
      ] and involvement of the RIG-I pathway in IL-1β production [
      • Poeck H.
      • Bscheider M.
      • Gross O.
      • Finger K.
      • Roth S.
      • Rebsamen M.
      • et al.
      Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin-1β production.
      ] suggest that inflammasomes may play role in HCV and other forms of viral hepatitis.

      Liver fibrosis

      Chronic liver inflammation, that is amplified by IL-1, leads to fibrosis and cirrhosis. In rats, IL-1Ra administration attenuated dimethylnitrosamin (DMN)-induced liver cirrhosis [
      • Mancini R.
      • Benedetti A.
      • Jezequel A.M.
      An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver.
      ] and IL-1R-deficient mice were protected from thioacetamide (TAA)-induced fibrogenesis [
      • Gieling R.G.
      • Wallace K.
      • Han Y.P.
      Interleukin-1 participates in the progression from liver injury to fibrosis.
      ]. The expression of MMP9, MMP13, and TIMP, regulators of fibrosis and tissue remodeling, is IL-1-dependent [
      • Gieling R.G.
      • Wallace K.
      • Han Y.P.
      Interleukin-1 participates in the progression from liver injury to fibrosis.
      ]; however, the exact mechanisms by which IL-1R signaling promotes fibrosis and the cell type(s) that produce(s) IL-1β are yet to be fully defined. Hepatic stellate cells expressed components of the inflammasome and activation of primary mouse stellate cells or LX-2 HSC cells with MSU resulted in increased TGFβ and collagen-1 expression, actin reorganization, and inhibition of HSC chemotaxis in an NLRP3-dependent manner [
      • Watanabe A.
      • Sohail M.A.
      • Gomes D.A.
      • Hashmi A.
      • Nagata J.
      • Sutterwala F.S.
      • et al.
      Inflammasome-mediated regulation of hepatic stellate cells.
      ]. In a carbon-tetrachloride (CCl4) and TAA-induced in vivo liver fibrosis model, expression of TGFβ and collagen-1 was significantly reduced in mice lacking either NLRP3 or the adaptor molecule ASC [
      • Watanabe A.
      • Sohail M.A.
      • Gomes D.A.
      • Hashmi A.
      • Nagata J.
      • Sutterwala F.S.
      • et al.
      Inflammasome-mediated regulation of hepatic stellate cells.
      ]. Additional data from the CCl4-induced fibrosis model indicated that IL-1Ra protected mice from acute hepatocyte damage and promoted hepatocyte proliferation [
      • Zhu R.Z.
      • Xiang D.
      • Xie C.
      • Li J.J.
      • Hu J.J.
      • He H.L.
      • et al.
      Protective effect of recombinant human IL-1Ra on CCl4-induced acute liver injury in mice.
      ]. In an animal model of NASH, inhibition of hepatic cell death with a pan-caspase inhibitor suppressed fibrosis [
      • Witek R.P.
      • Stone W.C.
      • Karaca F.G.
      • Syn W.K.
      • Pereirea T.A.
      • Agboola K.M.
      • et al.
      Pan-Caspase inhibitor VX-166 reduces firbosis in an animal model of nonalcoholic steatoehaptitis.
      ]. The specific role of caspase-1 versus other caspases is yet to be fully understood in liver fibrosis.

      Other liver diseases

      While the characterization of the role of inflammasomes in autoimmune hepatitis is still under investigation, increased serum IL-1β levels were found in patients with primary biliary cirrhosis (PBC) [
      • Barak V.
      • Selmi C.
      • Schlesinger M.
      • Blank M.
      • Aqmon-Levin N.
      • Kalickman I.
      • et al.
      Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis.
      ].
      Although parasitic schistosomiasis is rare in the Western world, it is common in Africa, Asia, and South America. Schistosoma mansoni egg antigens were shown to induce NLRP3 inflammasome activation and IL-1β secretion from macrophages via Dectin-2, ROS production and potassium efflux [
      • Ritter M.
      • Gross O.
      • Kays S.
      • Ruland J.
      • Nimmerjahn F.
      • Saijo S.
      • et al.
      Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses.
      ], and NLRP3-deficient mice exhibited decreased immunopathology and smaller granulomas following S. mansoni infection [
      • Ritter M.
      • Gross O.
      • Kays S.
      • Ruland J.
      • Nimmerjahn F.
      • Saijo S.
      • et al.
      Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses.
      ].
      IL-1β gene polymorphisms were found to influence the susceptibility of developing HCC in chronic liver diseases [
      • Sakamoto T.
      • Higaki Y.
      • Hara M.
      • Ichiba M.
      • Horita M.
      • Mizuta T.
      • et al.
      Interaction between interleukin-1beta -31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese.
      ]. Another study found that caspase-1 expression was downregulated in hepatocellular carcinoma [
      • Fujikawa K.
      • Shiraki K.
      • Sugimoto K.
      • Ito T.
      • Yamanaka T.
      • Takase K.
      • et al.
      Reduced expression of ICE/caspase1 and CPP32/caspase3 in human hepatocellular carcinoma.
      ]. However, Yan et al. found higher caspase-1 activity both in human HCC and in hepatoma cell lines exposed to hypoxia [
      • Yan W.
      • Chang Y.
      • Liang X.
      • Cardinal J.S.
      • Huang H.
      • Thorne S.H.
      • et al.
      High mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases.
      ]. In addition, IL-18 has been reported to promote hepatic metastases of melanoma via the adhesion molecule VCAM-1 [
      • Vidal-Vanaclocha F.
      • Fantuzzi G.
      • Mendoza L.
      • Fuentes A.M.
      • Anasagasti M.J.
      • Martin J.
      • et al.
      IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1.
      ].
      IL-1 and inflammasome activation may be related to complications of liver diseases. For example, in addition to contributing to the development of liver injury, inflammation and fibrosis, IL-1β, IL-18, and the inflammasomes may also mediate encephalopathy. Caspase-1 and IL-18 levels were higher in patients with acute or acute-on-chronic liver failure compared to controls or patients with stable chronic liver diseases [
      • Roth G.A.
      • Faybik P.
      • Hetz H.
      • Hacker S.
      • Ankersmit H.J.
      • Bacher A.
      • et al.
      Pro-inflammatory interleukin-18 and Caspase-1 serum levels in liver failure are unaffected by MARS treatment.
      ]. Furthermore, the onset of hepatic encephalopathy in toxic liver injury was delayed in IL-1R KO mice [
      • Bémeur C.
      • Qu H.
      • Desjardins P.
      • Butterworth R.F.
      IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure.
      ]. The role of local inflammasome activation and IL-1β in the brain was demonstrated in various forms of cognitive and brain diseases, such as Alzheimer’s disease, and in alcohol-related behavioral changes [
      • Halle A.
      • Hornung V.
      • Petzold G.C.
      • Stewart C.R.
      • Monks B.G.
      • Reinheckel T.
      • et al.
      The Nalp3 inflammasome is involved in the innate immune response to amyloid-beta.
      ,
      • Alfonso-Loeches S.
      • Pascual-Lucas M.
      • Blanco A.M.
      • Sanchez-Vera I.
      • Guerri C.
      Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage.
      ].
      Finally, in auto-inflammatory syndromes, such as the macrophage activation syndrome (MAS), hepato-splenomegaly and abnormal liver function tests can occur and some of these auto-inflammatory diseases improve with anti-IL-1 therapy [
      • Dinarello C.A.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      ]. Case reports documented successful treatment of MAS with anakinra [
      • Kelly A.
      • Ramanan A.V.
      A case of macrophage activation syndrome successfully treated with anakinra.
      ], however, in some rare cases, the onset of MAS [
      • Lurati A.
      • Teruzzi B.
      • Salmaso A.
      • Demarco G.
      • Pontikati I.
      • Gattinara M.
      • et al.
      Macrophagic activation sindrome (MAS) during anti-IL1 receptor therapy (anakinra) in a patient affected by systemic onset idiopathic juvenile arthritis (soJIA).
      ] or acute hepatitis has also been reported after anakinra therapy [
      • Canna S.
      • Frankovich J.
      • Higgins G.
      • Narkewicz M.R.
      • Nash S.R.
      • Hollister J.R.
      • et al.
      Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist.
      ].

      Caveats in the evaluation of inflammasome activation in liver diseases

      Figure thumbnail fx7

      Alternative pathways of IL-1β cleavage

      While caspase-1 is the most important enzyme involved in the cleavage of pro-IL-1β into its mature form, other enzymes such as caspase-8 [
      • Maelfait J.
      • Vercammen E.
      • Janssens S.
      • Schotte P.
      • Haegman M.
      • Magez S.
      • et al.
      Stimulation of Toll-like receptor 3 and 4 induces interleukin-1β maturation by caspase-8.
      ] and neutrophil- and macrophage-derived serine proteases [
      • Netea M.G.
      • Simon A.
      • van de Veerdonk F.
      • Kullberg B.J.
      • Van der Meer J.W.
      • Joosten L.A.
      IL-1beta processing in host defense: beyond the inflammasomes.
      ,
      • Dinarello C.A.
      Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
      ] cleave pro-IL-1β. This may explain that while IL-1β deficiency prevented inflammation in some sterile inflammation models, the lack of caspase-1 was not protective [
      • Netea M.G.
      • Simon A.
      • van de Veerdonk F.
      • Kullberg B.J.
      • Van der Meer J.W.
      • Joosten L.A.
      IL-1beta processing in host defense: beyond the inflammasomes.
      ]. In addition, the functional importance of IL-1β and IL-18 may be distinct in different tissues and cell types. This notion is supported by recent data suggesting a prominent role for IL-18 in intestinal homeostasis, while IL-1β seems to play a bigger role in liver diseases.

      Tissue- and cell-specific expression and role of inflammasomes

      Given the multiple functions and distinct tissue and cell distribution [
      • Kummer J.A.
      • Broekhuizen R.
      • Everett H.
      • Agostini L.
      • Kuijk L.
      • Martinon F.
      • et al.
      Inflammasome components NALP1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response.
      ] of the inflammasomes, they may have different roles in different tissues. For example, while inflammasomes and caspase-1 induced cell death, pyroptosis, and pyronecrosis in macrophages, caspase-1 was found to promote cell survival in HeLa and CHO cell lines [
      • Gurcel L.
      • Abrami L.
      • Girardin S.
      • Tschopp J.
      • van der Goot F.G.
      Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival.
      ]. Moreover, even though the NLRP3 inflammasome is important for the maintenance of the intestinal barrier and protection against colitis [
      • Zaki M.H.
      • Boyd K.L.
      • Vogel P.
      • Kastan M.B.
      • Lamkanfi M.
      • Kanneganti T.D.
      The NLRP3 inflammasome protects against loss of epithelial intergrity and mortality during experimental colitis.
      ], it can still contribute to inflammation in gut immune cells. Cell specificity of inflammasomes has particular relevance to liver diseases where increased gut permeability contributes to the pathogenesis.

      ASC is not just a passive adaptor

      ASC is necessary for the formation of many (but not all) inflammasome complexes. There is increasing evidence that ASC has inflammasome-independent functions, for example in lymphocyte migration and antigen presentation of dendritic cells [
      • Ippagunta S.K.
      • Malireddi R.K.
      • Shaw P.J.
      • Neale G.A.
      • Walle L.V.
      • Green D.R.
      • et al.
      The inflammasome adaptor ASC regulate the function of adaptive immune cells by controlling Dock-2 mediated Racactivation and actin polymerization.
      ] as well as in regulation of MAPK activity and chemokine expression [
      • Taxman D.J.
      • Holley-Guthrie E.A.
      • Huang M.T.
      • Moore C.B.
      • Bergstralh D.T.
      • Allen I.C.
      • et al.
      The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome.
      ].

      “Non-canonical” functions of caspase-1 [56]

      Beyond its role in IL-1β, IL-18, IL-33 cleavage, regulation of caspase-7, and cell death, caspase-1 was shown to be necessary for release of HMGB1, a major DAMP [
      • Vande W.L.
      • Kanneganti T.D.
      • Lamkanfi M.
      HMGB1 release by inflammasomes.
      ].

      Caspase-11 in non-canonical inflammasome activation

      Recently, Kayagaki et al. have reported that caspase-11 (human caspase-4 and -5) triggers caspase-1-independent macrophage death and caspase-1-dependent IL-1β and IL-18 production in response to certain inflammasome activators, including CTB, Escherichia coli, Citrobacter rodentium, Vibrio cholera [
      • Kayagaki N.
      • Warming S.
      • Lamkanfi M.
      • Walle L.V.
      • Louie S.
      • Dong J.
      • et al.
      Non-canonical inflammasome activation targets caspase-11.
      ].

      NLRP6: a “new” inflammasome

      To date, mostly four main prototypes of inflammasomes have been characterized, but there are other NLRs, such as the recently discovered NLRP6, that have uniquely increased levels in the liver compared to the spleen [
      • Lech M.
      • Avila-Ferrufino A.
      • Skuginna V.
      • Susanti H.E.
      • Anders H.J.
      Quantitative expression of RIG-like helicase, NOD-like receptor and inflammasome-related mRNAs in humans and mice.
      ]. Recent evidence suggests that NLRP6 is a key component in the maintenance of epithelial cell integrity [
      • Elinav E.
      • Strowig T.
      • Kau A.L.
      • Henao-Meija J.
      • Thaiss C.A.
      • Booth C.J.
      • et al.
      NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis.
      ] and its role in liver diseases associated with increased gut permeability deserves investigations.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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