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Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and aging (CHROMETA), University of Leuven, Leuven, BelgiumDepartment of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
Cirrhosis is a multisystemic disease wherein inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to bacterial infections, which may precipitate acute decompensation and acute-on-chronic liver failure, both of which are associated with high short-term mortality. Innate immune cells are an essential first line of defence against pathogens. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes in the liver, and promote tissue damage. During cirrhosis progression, damage- and pathogen-associated molecular patterns activate immune cells and promote development of systemic inflammatory responses which may involve different tissues and compartments. The antibacterial function of circulating neutrophils and monocytes is gradually and severely impaired as cirrhosis worsens, contributing to disease progression. The mechanisms underlying impaired antimicrobial responses are complex and incompletely understood. This review focuses on the continuous and distinct perturbations arising in innate immune cells during cirrhosis, including their impact on disease progression, as well as reviewing potential therapeutic targets.
We read with great interest the review article “Innate immune cells in cirrhosis” by Bernsmeier et al.1 We strongly agree on the important role of innate immune cells, especially monocytes and macrophages viz. Kupffer cells, in the development and progression of liver cirrhosis and complications such as acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Even though the review is very comprehensive, we think it is missing a section on macrophage biomarkers to further support the role of macrophages in cirrhosis development and progression including complications.
Cirrhosis is a multisystem disease that develops as a result of chronic liver injury when healthy parenchyma is progressively replaced by fibrotic tissue. The consequences of cirrhosis stem not only from hepatocyte loss or portal hypertension but also from continuous local and systemic inflammation that further perpetuates liver injury and leads to increased susceptibility to infection and risk of organ failure.
From a clinical perspective, analysis of natural history studies showed that prognosis in cirrhosis correlated with clinically recognisable stages, as patients progressed from compensated to decompensated cirrhosis. In compensated cirrhosis, in the absence of ascites or bleeding oesophageal varices, liver-related mortality remained low, but it dramatically increased as ascites, variceal bleeding and bacterial infections developed.
According to this concept, immune dysfunction in cirrhosis can be viewed as a continuum that starts with the onset of chronic hepatic inflammation, worsens with the development of cirrhosis and portal hypertension, is further aggravated by bacterial translocation and may finally culminate in complete immune exhaustion in acute-on-chronic liver failure (ACLF
Immune dysfunction in cirrhosis mainly involves components of the innate immune system. This system is widely distributed throughout human tissue compartments and represents the first line of defence against pathogens. Innate immunity is critical to maintain homeostasis by preventing microbe invasion, by regulating appropriate responses to sterile injury, and by shaping adaptive immunity through antigen presentation. The innate immune system is composed of physical and chemical barriers, involving humoral and cell-mediated components. In cirrhosis, knowledge has been accumulating regarding the involvement of subsets of innate immune cells in immune dysfunction. Evidence now suggests that specifically neutrophils, monocytes, macrophages and dendritic cells and to a lesser extent eosinophils, basophils, mastocytes, innate lymphoid cells, and mucosal-associated invariant T (MAIT) cells actively contribute to inflammation and susceptibility to infection.
In this review, we aim to elaborate on the importance of innate immune cells in cirrhosis and the associated multisystem inflammatory state. We introduce the concept that the natural history of cirrhosis and the development of its complications can be explained by evolving immune dysfunction from the onset of chronic liver disease to end-stage decompensated cirrhosis; we propose that a better understanding of immune dysfunction at the molecular level may help to develop novel therapeutic approaches.
Immune activation in chronic liver disease evolves from chronic liver injury of any aetiology, long before the onset of fibrosis or cirrhosis. In parallel to inflammation restorative immune cell populations infiltrate the liver. However, if resolution of inflammation does not occur, cirrhosis evolves characterised by hepatic and systemic inflammation.
Neutrophil host defence activities
Neutrophils represent the largest family of circulating leucocytes and are the first cells mobilised during tissue injury. They play a key role in inflammation and host defence against pathogens (bacteria, yeasts, fungi). Their anti-infectious function requires various rapid and temporally coordinated activities which are triggered upon activation of specific receptors, regulating neutrophil migration into tissues, pathogen sensing, recognition and killing.
Briefly, proinflammatory agents (tumour necrosis factor alpha [TNFα], interleukin [IL]-1, IL-17, histamine, lipopolysaccharide [LPS]) generated in inflamed or infected tissues induce a local increase of the vascular permeability and stimulate the expression of adhesion molecules, such as E-selectin, P-selectin (also expressed by activated platelets) and members of the integrin superfamily (intercellular adhesions molecules [ICAMs], vascular cell adhesion molecules [VCAMs]), at the luminal surface of endothelial cells. Selectins reduce the speed of movement of circulating neutrophils in flow (rolling) by interacting with their constitutively expressed receptors (PSGL1 [P-selectin ligand 1] and L-selectin).
This rolling step is further amplified by the redistribution of PSGL1 and L-selectin induced by the interaction of E-selectin with CD44 on neutrophils. ICAM-1 and ICAM-2 then interact with the neutrophil 2-subfamily receptors (CD11a, CD11b, CD11c/Cd18) to induce firm adhesion of neutrophils to the endothelium.
This step is essential for diapedesis, a short process (<10 min) regulated by various chemoattractants (C5a, Paf, LTB4, n-formylated peptides, IL8, IL6, SDF1α), which control neutrophil migration speed (chemokinesis), polarity and direction (chemotaxis).
Once in tissues, neutrophils capture pathogens either by direct interaction with them or indirectly via Fc receptors, FcγRIIA (CD32) and FcγRIIIB (CD16), and complement receptors, CR1 (CD35) and CR3, and CD11b/CD18 integrin. Signalling events triggered by these opsonin receptors induce a series of coordinated antibacterial responses such as the engulfment of pathogens into phagosomes (phagocytosis) and the release of antibacterial agents stored in azurophilic, specific and tertiary granules (degranulation or exocytosis) including proteases (elastase, cathepsin G, lysozyme), myeloperoxidase (MPO), and defensins. Simultaneously, NADPH oxidase 2 (NOX2) complex is activated at the plasma membrane and massively generates superoxide anion (O2.-) respiratory burst) which is essential for bacterial killing.
Superoxide is immediately converted into more toxic reactive oxygen species (ROS), i.e. OH-, H2O2, 1O2 (singlet oxygen), hypochloric acid (HOCl)/bleach water, (NaOCl) and chloramine (R-NHCL). H2O2 is used by MPO to halogenate proteins, which enhances bactericidal activity.
Finally, large strands of decondensed DNA are extruded from dying neutrophils, carrying with them mainly cationic proteins of cytosolic and granular origin (elastase, cathepsin G, lactoferrin, MPO). These structures called neutrophil extracellular traps (NETs) capture and destroy pathogens.
Degranulation and respiratory burst are also stimulated by soluble inflammatory agents including conventional chemoattractants (formyl-peptides, C5a, Paf, LTB4), chemokines (IL6, IL8, IL33) and proinflammatory mediators, (LPS, TNFα, Toll-like receptor [TLR] agonists), which potentiate bacterial destruction.
In healthy individuals, the defence activities of neutrophils are harmoniously coordinated and regulated, leading to rapid bacterial eradication, resolution of inflammation and tissue preservation. During cirrhosis development, neutrophil responses are modified over time, leading to compromised bacterial elimination and disease progression.
Neutrophils move from an aggressive to a paralysed state during cirrhosis development
During cirrhosis development (Child-Pugh A, B and C), systemic inflammation persists with high serum levels of proinflammatory cytokines (TNFα, IL-1β, IL-6, IL-17, IL-18, interferon-gamma [IFNγ]), soluble receptors (sTNFRI, IL1sRI, IL1Ra, sCD14, Fas-R), endothelial activation markers (ICAM-1, VCAM-1, vascular endothelial growth factor [VEGF], nitrates/nitrites) and neutrophils overexpressing CD11b and CD62L (LSEL) but decreased L-selectins.
This is consistent with weak antibacterial activities (ROS production, MPO release, bacterial killing) induced by formylpeptide in neutrophils from patients with acute decompensation (AD) (Child-Pugh C) and high levels of white blood cells (WBCs 7.6–9.6×103 cell/μl).
). These neutrophil modifications were not related to the aetiology of cirrhosis (hepatitis B/C, alcohol-related liver disease [ALD]) nor gastrointestinal bleeding and serum levels of glutamic-pyruvate transaminase (GPT) or alkaline phosphatase.
Changes in innate immune cell differentiation and function have been associated with different stages of cirrhosis. In some immune cell populations (neutrophils, monocytes, macrophages), failure to repel microbial challenge worsens with disease severity. In vitro and in vivo data suggest that the underlying mechanisms involve hepatocellular failure and death, continued hepatic and systemic inflammation and pathological bacterial translocation from the gut.
Paradoxically, basal neutrophil ROS production is increased in some decompensated patients
However, its intensity remained relatively weak and raised questions about its relevance to bacterial killing, which requires massive ROS production. The increased basal ROS production during disease progression and defective phagocytic activity of neutrophils in decompensated patients were associated with a greater risk of infection, organ failure and short-term mortality.
This deficiency may raise concerns about mTOR metabolic activities and about mTOR antagonist (rapamycin)-based therapy of immunocompromised patients. A defective IL33/ST2 signalling pathway associated with overexpression of G protein-coupled receptor kinase 2 (GRK2) was involved in the defective IL8-mediated migration of neutrophils from patients with decompensated cirrhosis (Child-Pugh B/C, WBC count 6–11×103cells/μl).
The impairment of neutrophil's defence function comprises both intracellular and extracellular alterations. The intrinsic neutrophil impairments reported above (Table 1) can be reproduced with pathological concentrations of various agents present in patient serum such as bilirubin,
During the development of cirrhosis, neutrophils are subjected to biochemical changes and impairment of their anti-infectious function which worsens according to the disease severity. In the severe stages of cirrhosis (acute decompensation), many cellular activities that support host defence function are highly deficient including the parameters regulating the diapedesis, bacterial recognition and various killing activities including bacterial engulfment/phagocytosis, degranulation (exocytosis), the massive and rapid production of reactive oxygen species (respiratory burst) and NETs. These functional deficiencies are associated with impaired intracellular signalling and protein expression, and partly explain the high susceptibility of patients to microbial infections. AD, acute decompensation; NET, neutrophil extracellular trap; PLC, phospholipase C; ERK, extracellular signal-regulated kinase 1/2; MAPK, mitogen-activated protein kinases; GRK2, G protein-coupled receptor kinase 2; ND, not determined.
Therapeutic approaches to improve neutrophil antibacterial responses and reduce susceptibility to infection
Recent ex vivo studies with potent TLR7/8 agonists (CL097, R848) show that the deficient degranulation, ROS production and bacterial killing by neutrophils from patients with cirrhosis can be rapidly corrected in vitro providing evidence that intrinsic deficiencies are reversible in decompensated alcohol-related cirrhosis (Child-Pugh C)
which could have a particular role as adjunct therapy against antibiotic-resistant bacteria. Liver function could also benefit since ROS mediate macrophage M2 polarisation and orchestrate liver repair.
Deciphering the molecular basis of cirrhosis-associated protein depletion in neutrophils (adhesion molecules, mTOR, NOX2) is important for the development of interventions that preserve liver function and reduce severely affected patients' susceptibility to infection.
The deficient antimicrobial activities of neutrophils in decompensated cirrhosis can be reversed in vitro and in vivo with potent TLR7/8 agonists (R848) that stimulate signalling and protein synthesis (NOX2), and bacterial elimination.
Mononuclear phagocytes include monocytes, macrophages and dendritic cells and play a pivotal role in initiating innate immune responses. Their functions involve phagocytosis and killing of bacteria, antigen presentation, inflammatory cytokine production in response to bacterial challenge, as well as recruitment and activation of immune effector cells. Phagocytes regulate antimicrobial defence, perpetuation and cessation of inflammation and tissue injury, fibrogenesis and tumourigenesis, explaining their central role in the pathophysiology of immune dysfunction in patients with cirrhosis.
Regulation of monocytes along different stages of cirrhosis progression
The relationship between disease-specific differentiation/dysfunction of circulating monocytes and morbidity/mortality has been described in patients with AD and ACLF (compared to stable cirrhosis) and less frequently in those with chronic liver disease and compensated cirrhosis (compared to healthy individuals).
The first report of monocyte dysfunction in patients with cirrhosis goes back to a letter from 1979,
delineating the impaired phagocytic capacity of yeast in a study involving patients with biopsy-proven cirrhosis. Wasmuth et al. were the first to discover reduced expression of a major histocompatibility complex (MHC) class II receptor (human leucocyte antigen [HLA]-DR) on circulating monocytes from patients with ACLF, also showing that this reduced expression was associated with adverse prognosis.
In response to extracellular binding of pathogenic peptides, HLA-DR elicits T cell responses by activating the T cell receptor. HLA-DR expression is increased upon classical or alternative immune stimulation, illustrating its role as a monocyte activation marker. By contrast, HLA-DR downregulation occurs in states of acquired immunosuppressive monocyte differentiation induced by various stimuli.
in response to systemic inflammatory response syndrome (SIRS) and circulating pathogen-associated molecular patterns (PAMPs). Functionally M-MDSCs in cirrhosis were typified by distinct immunosuppressive properties, i.e. reduced T cell activation, TNF-α/IL-6 production in response to TLR stimulation and phagocytic capacity.
Recently, TAM receptors (protein tyrosine kinase 3 [TYRO-3], anexelekto [AXL], Mer receptor tyrosine kinase [MERTK]), which are important regulators of innate immune homeostasis that inhibit TLR signalling pathways and promote phagocytic removal of apoptotic cells,
have been implicated in innate immune dysfunction in cirrhosis. In parallel with advancing cirrhosis and portal hypertension prior to AD and ACLF, a circulating immunoregulatory population of distinct AXL-expressing (CD14+HLA-DR+AXL+) monocytes expanded. These monocytes were characterised by preserved phagocytic capacity but reduced T cell activation and TNF-α/IL-6 production in response to TLR stimulation.
In AD and ACLF, the emergence of a MERTK-expressing circulating monocyte population (CD14+HLA-DR+MERTK+) that dampened innate immune responses to microbial challenge was associated with disease severity and adverse outcomes,
RNA-seq analysis has shown that monocytes in ACLF have a distinct transcriptional profile compared to those in decompensated cirrhosis. It was also shown recently that glutamine metabolism regulated monocyte functions, such as phagocytic capacity and cytokine production.
As outlined, the phagocytic capacity of monocytes seems to be maintained throughout disease progression to decompensated cirrhosis, but was reduced at the stage of AD and ACLF potentially due to the expansion of M-MDSCs.
In contrast to neutrophils, bacterial killing and oxidative burst capacity have been differentially reported, but seemed to remain preserved throughout all stages of cirrhosis, except for monocytes from patients with alcohol-related liver disease and active drinking.
The differentiation of circulating monocytes in patients with cirrhosis is continually adapting to the current inflammatory milieu, which is characterised by continual PAMP and DAMP exposure that increases with disease severity, activation and death of other circulating immune cells and SIRS at the stage of infection and subsequent AD and ACLF. The modulation of the milieu over time seems to generate immunoregulatory monocytic populations that expand over the course of compensated to decompensated disease, and then immunosuppressive populations that expand with the onset of liver failure. The hypothetical aim of monocyte plasticity in cirrhosis is to restore systemic and compartmental immune homeostasis but this increases the risk of systemic or compartmental infectious complications (Fig. 3).
In advanced cirrhosis and ACLF distinct immunoregulatory and immunosuppressive populations of circulating monocytic cells evolve in relation to disease severity, amongst CD14++CD16+, M-MDSC, and monocytes expressing AXL and MERTK, respectively.
Liver infiltrating monocytes
Monocytes in the liver may represent circulating monocytes trafficking through the sinusoids (CD14+CD68−). Moreover, migrating monocytes either remain as monocytes within the tissue, acquiring antigen-presenting capability, or mature into macrophages.
In the cirrhotic liver, CD14++CD16+ monocytes were increased, accumulated at sites of inflammation/fibrosis and were characterised by enhanced phagocytosis, antigen presentation, T cell activation, and secretion of chemokines, growth factors, proinflammatory and profibrogenic mediators (that activated hepatic stellate cells [HSCs]). CD14++CD16+ cells hereby contributed to the perpetuation of hepatic inflammation and fibrogenesis.
Their presence was due to increased CX3CR1 dependent migratory potential, and maturation from CD14++CD16− monocytes. It has been proposed that proinflammatory CD14++CD16+ cells may transmigrate back to the circulation and contribute to SIRS responses, whereas anti-inflammatory monocytes remain in the liver, suppress T cells and promote endotoxin tolerance.
Triggering receptor expressed on myeloid cells 1 (TREM-1) was highly upregulated on circulating monocytes, monocyte-derived macrophages and Kupffer cells (KCs) in patients with fibrosis and promoted hepatic inflammation and fibrosis in a mouse model of cirrhosis.
Recently, Rachamandran et al. investigated monocyte and macrophage heterogeneity using scRNAseq in healthy and cirrhotic human livers and defined a novel scar-associated profibrogenic TREM2+CD9+ macrophage subpopulation, that differentiated from circulating monocytes.
Given the association of monocyte dysfunction with infectious complications that may accelerate morbidity and mortality from cirrhosis, several potential targets for immunotherapy have been defined. There are a number of proof of concept studies, but few treatment options are under clinical evaluation (Table 2). Concepts and substances with potential therapeutic use are inhibitors of TAM receptors (AXL/MERTK),
Therapy with the glycoprotein G-CSF is a potentially interesting concept to improve liver regeneration and innate immune responses in cirrhosis by releasing bone marrow-derived CD34+ haematopoietic stem cells in order to replace dysfunctional circulating innate immune cells (granulocytes, monocytes, dendritic cells) with functional counterparts. Clinical investigations revealed differential results in respect to fibrosis resolution, regeneration, liver function, adverse events and survival.
Mobilises CD34+ haematopoietic stem cells from the bone marrow, with the capacity to differentiate into multiple cell lineages and replace dysfunctional circulating innate immune cells (granulocytes, monocytes, dendritic cells)
As the key metabolic organ, the liver is strategically placed to drain the abdominal organs through the portal vein and receive systemic blood via the hepatic artery. The large sinusoidal network lined by highly permeable fenestrated endothelial cells exposes hepatocytes to the content of plasma that includes gut-derived bacterial products. To prevent immune activation in healthy KCs, LSECs and liver dendritic cells (DCs) actively promote tolerance by effectively removing bacterial products and secreting tolerogenic factors. KCs and liver DCs regulate this microenvironment by constitutively secreting IL-10.
KCs phagocytose and scavenge DAMPs, released during hepatic tissue injury, through cell surface receptors. These include ATP, uric acid, DNA fragments, cholesterol crystals and high mobility group box 1. They also effectively recognise PAMPs and remove circulating bacteria, preventing systemic immune activation.
Hepatic innate immune cells continue to release cytokines and chemokines, attracting inflammatory cells from the circulation. Chronic injury and inflammasome activation alter the phenotype of LSECs. Changes in the local microenvironment including the composition of hyaluronan, increased adhesion molecules such as leucocyte CD44 and CD18, and chemokines allow extravasation of immune cells across the sinusoidal endothelial barrier.
On the one hand, hepatocyte loss worsens and hepatocellular failure ensues, leading to decreased complement, acute-phase proteins and albumin, which results in defective bacterial opsonization and impaired clearance of bacterial products. On the other hand, KCs are continuously activated during the progression of chronic liver disease, initially by DAMPs released by dying hepatocytes. Activated TLR4/CRIg-expressing KCs lose their tolerogenic phenotype and continue to secrete proinflammatory cytokines and chemokines including MCP-1/CCL2
that amplify the immune response, recruiting bone marrow-derived monocytes and neutrophils to the liver. Monocyte-derived macrophages may in fact become the dominant phagocytic cell population in the diseased liver. As cirrhosis worsens, bacterial product translocation increases from the gut.
In the final stage, the development of portal hypertension, continuous hepatocyte loss and local and systemic immune cell activation set the stage for immune exhaustion, the development of bacterial infections, organ dysfunction and progressive hepatocyte failure.
Recently, MERTK-expressing monocytes and macrophages were identified in the circulation but also in the liver and other tissue sites, such as the peritoneum and lymph nodes in patients with AD, and especially those with ACLF. HLA-DR+MERTK+ monocytes represent an immunomodulatory pro-restorative cell population, characterised by enhanced efferocytosis of apoptotic neutrophils. However, this population show blunted cytokine responses when exposed to LPS,
and likely originate in the anti-inflammatory/tolerogenic environment prevailing in ACLF. MERTK-expressing macrophages may contribute to resolution of inflammation and restoration at the tissue level, which may be particularly relevant in the fibrotic/cirrhotic liver, but may aggravate systemic immunoparesis by reverse migration.
The development of cirrhosis has immunological consequences extending far beyond the liver. The intestine is one of the most immunologically affected and clinically relevant sites in cirrhosis, as progressive intestinal barrier dysfunction in advanced cirrhosis enables translocation of bacterial products to the liver, peritoneum and systemic circulation that may clinically manifest as spontaneous bacterial peritonitis, worsening encephalopathy, bacteraemia and sepsis. Recently activated CD14+Trem1+iNOS+ intestinal macrophages were observed in the duodenum of patients with decompensated cirrhosis undergoing screening for varices. These cells likely represent monocyte-derived intestinal macrophages that are attracted to the gut in response to MCP-1 which is released by the intestinal epithelium in response to increased bacterial translocation.
In murine models of cirrhosis, the mucus layer is reduced in thickness, with a loss of goblet cells and decreased MUC2 expression. This is associated with bacterial overgrowth in the inner most mucus layer. The closer proximity of bacteria to epithelial cells, a deficiency of Paneth cell defensins, as well as a defective vascular barrier likely all contribute to the passage of bacterial products in cirrhosis.
Circulating monocytes, monocyte-derived macrophages in liver and other tissues and tissue macrophages have site-specific differentiation: this implies that alongside immunosuppressive populations prevailing in the systemic circulation, activated proinflammatory monocytes may prevail in tissues such as the gut in the same patient.
Gut-resident macrophages represent a heterogeneous mix of CX3CR1-expressing cells strategically positioned within the different layers of the intestine. In the lamina propria (LP), these macrophages actively contribute to host defence and barrier integrity coupled with high phagocytic activity. Cx3cr1−/− mice have reduced numbers of intestinal macrophages and show increased bacterial translocation.
It has been shown that CD103(+)-DCs were activated with heightened phagocytosis and migration in rats with experimental cirrhosis but no evidence of bacterial translocation, whereas these functions were paralysed in infected rats.
Recent fate mapping and single-cell sequencing experiments in genetically modified mice showed that self-renewing LP macrophages reside in specialised niches that function to support the epithelial and vascular barrier.
It is tempting to speculate that selective depletion of these specialised LP macrophage niches in cirrhosis is a key factor in the loss of epithelial and vascular barrier integrity. However, it is also possible that constant immune activation with an influx of monocyte-derived macrophages into the LP may be detrimental to barrier integrity, as these cells may secrete factors such as nitric oxide, IL-6 and IL-8 that may contribute to increased permeability.
and liver in the early stages of biliary cirrhosis, which was associated with mastocyte infiltration and hepatic expression of IL-6, IFNγ, TGFβ, and IL-2 and the granulopoietic-stimulating factor IL-5. Infiltrating eosinophils degranulate major cationic proteins, eosinophil cationic protein; major basic protein and eosinophil-derived neurotoxin, consistent with a role in primary biliary cirrhosis.
The role of basophils during cirrhosis progression has barely been studied.
DCs operate at the interface between the innate sensing of pathogens and the activation of adaptive immunity. The role of DCs in human cirrhosis remains underexplored. Circulating DCs that cross hepatic sinusoids to reach afferent lymphatics are educated by the hepatic tolerogenic microenvironment to adopt a regulatory phenotype.
Mastocytes are haematopoietic sentinel cells that reside in connective tissues and participate in many pathophysiological processes through production of various mediators released in part from their numerous granules. In addition to their role in IgE-dependent allergy, they induce liver damage and HSC activation during progression to fibrosis/cirrhosis in mice
and are derived from the lymphoid lineage. They mirror T cells but do not express acquired antigen receptors or undergo clonal expansion. ILCs do not express myeloid- or DC markers but respond to signals from infected/injured tissues, initiate immune responses and regulate immune homeostasis
A detailed characterisation of their phenotype, tissue-residency and functionality in human liver revealed that ILC3s account for the majority of intrahepatic ILCs. The frequency of ILC2s, sparsely present in non-fibrotic livers, increased in parallel with fibrosis severity where they secreted the pro-fibrotic cytokine IL-13 and amphiregulin.
Mucosal-associated invariant T (MAIT) cells are a subset of non-conventional T cells abundant in human blood, gut, and liver that display innate, effector-like qualities. MAIT cells are activated by bacterial metabolites (riboflavin) via the MHC class I-related molecule (MR1). They modulate host defences and inflammation by producing inflammatory cytokines and via granzyme B-mediated killing of infected cells.
Circulating and hepatic MAIT cells were reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis, while they accumulated in liver fibrotic septae. Functionally, they were activated and profibrogenic in their interactions with HSCs. Prophylactic antibiotic therapy in decompensated cirrhosis was associated with higher MAIT cell frequency, and decreased activation.
Mediators generated by injured liver and resident cells promote the recruitment of phagocytes which aggravate liver damage, and alter distant tissue homeostasis which in turn impact on liver function/regeneration via molecular and cellular mediators.
Interconnections between innate immune cells and compartments
The innate and adaptive immune systems interact to produce proinflammatory and antibacterial agents that protect tissues against pathogens. In health, the liver is central to the elimination of bacteria/bacterial products from the intestines (such as LPS, peptides, nucleic acid fragments) and endogenous factors released following tissue injury. Liver dysfunction associated with hepatocellular failure and constant immune activation alters immune function in distant organs (Fig. 1), which in turn fuels systemic inflammation, impacting the liver, and ultimately fuelling a vicious cycle. Some examples of pro-/anti-inflammatory crosstalk between innate immune cells, tissues, and mediators are summarised in Table 3. Major crosstalk occurs when pathological recruitment of circulating neutrophils, eosinophils and monocytes follows the onset of chronic inflammation in the liver. This process is mediated by activated KCs, LSECs, HSCs, resident mastocytes, and adipocytes which produce vaso-permeating agents and chemoattractants, facilitating tissue infiltration of recruited phagocytes and inducing tissue damage.
As cirrhosis develops, disruption of the intestinal barrier and failure to clear bacterial products by intestinal macrophages further activate liver immune cells. By the time portal hypertension develops, bacterial products are also shunted into the systemic circulation, maintaining inflammation.
Future immunotherapy has been proposed in order to restore innate immune function in cirrhosis hereby preventing infectious complications, decompensation, and potentially the need for transplantation, and death. Potential targets include TLR7/8, TLR3, TAM receptors and glutamine synthase.
Table 3Interconnections between innate immune cells, and compartments in liver diseases.
Mediators – pathophysiological consequences
CCL2 released by activated KC promotes monocyte infiltration into liver and damage in cirrhosis