- •Myeloid Gsk3β promotes liver pro-inflammatory immune responses to ischemia reperfusion.
- •Active Gsk3β inhibits AMPK activation and SHP induction in activated macrophages.
- •Gsk3β regulates AMPK/SHP independent of its S9 phosphorylation status.
Background & Aims
Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.
We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.
Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase–Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia–reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK–SHP pathway by liver ischaemia was demonstrated in tumour resection patients.
Gsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.
Glycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.
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- Liver ischemia and reperfusion injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation.Am J Transplant. 2011; 11: 1563-1569
- Innate immune mechanisms in ischemia/reperfusion.Front Biosci. 2009; 1: 91-98
- Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury.Transplantation. 2008; 85: 1016-1022
- HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling.J Exp Med. 2007; 204: 2913-2923
- The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion.J Exp Med. 2005; 201: 1135-1143
- Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice.Hepatology. 2011; 54: 999-1008
- Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.J Immunol. 2005; 175: 7661-7668
- Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.J Immunol. 2004; 173: 7115-7119
- Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury.Hepatology. 2010; 51: 621-632
- NLRP3 regulates neutrophil functions and contributes to hepatic ischemia-reperfusion injury independently of inflammasomes.J Immunol. 2014; 192: 4342-4351
- The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways.Prog Neurobiol. 2006; 79: 173-189
- Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3).Trends Immunol. 2010; 31: 24-31
- GSK3 inhibitors: development and therapeutic potential.Nat Rev Drug Discov. 2004; 3: 479-487
- GSK3: a multifaceted kinase in Wnt signaling.Trends Biochem Sci. 2010; 35: 161-168
- Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation.Nature. 2000; 406: 86-90
- Glycogen synthase kinase 3α-specific regulation of murine hepatic glycogen metabolism.Cell Metab. 2007; 6: 329-337
- GSK-3 inhibition: achieving moderate efficacy with high selectivity.Biochim Biophys Acta. 2013; 1834: 1410-1414
- Role that phosphorylation of GSK3 plays in insulin.EMBO J. 2005; 24: 1571-1583
- Glycogen synthase kinase 3: more than a namesake.Br J Pharmacol. 2009; 156: 885-898
- Glycogen synthase kinase 3: a point of convergence for the host inflammatory response.Cytokine. 2011; 53: 130-140
- Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.Nat Immunol. 2005; 6: 777-784
- Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in patients with decompensated cirrhosis.J Hepatol. 2011; 55: 784-793
- Inhibition of glycogen synthase kinase 3 beta ameliorates liver ischemia reperfusion injury by way of an interleukin-10-mediated immune regulatory mechanism.Hepatology. 2011; 54: 687-696
- Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death.Cell Death Dis. 2012; 3: e444
- The mPTP and its regulatory proteins: final common targets of signalling pathways for protection against necrosis.Cardiovasc Res. 2012; 94: 181-189
- GSK-3β at the crossroads in the signalling of heart preconditioning: implication of mTOR and Wnt pathways.Cardiovasc Res. 2011; 90: 49-56
- Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.J Clin Invest. 2004; 113: 1535-1549
- Role of glycogen synthase kinase-3β in cardioprotection.Circ Res. 2009; 104: 1240-1252
- Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism.J Hepatol. 2014; 61: 816-824
- Lithium exacerbates hepatic ischemia/reperfusion injury by inhibiting GSK-3β/NF-κB-mediated protective signaling in mice.Eur J Pharmacol. 2012; 697: 117-125
- Sirtuins and pyridine nucleotides.Circ Res. 2012; 111: 642-656
- CD154-CD40 T-cell costimulation pathway is required in the mechanism of hepatic ischemia/reperfusion injury, and its blockade facilitates and depends on heme oxygenase-1 mediated cytoprotection.Transplantation. 2002; 74: 315-319
- Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine.Transplantation. 1993; 55: 1265-1272
- CXCL10 regulates liver innate immune response against ischemia and reperfusion injury.Hepatology. 2008; 47: 207-214
- What turns CREB on?.Cell Signal. 2004; 16: 1211-1227
- The NF-κB family of transcription factors and its regulation.Cold Spring Harb Perspect Biol. 2009; 1: a000034
- AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease.Immunol Cell Biol. 2014; 92: 340-345
- AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration.Cell Metab. 2013; 18: 251-264
- Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype.J Immunol. 2008; 181: 8633-8641
- Inhibition of AMPK catabolic action by GSK3.Mol Cell. 2013; 50: 407-419
- Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome.Nat Commun. 2015; 6: 6115
- The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors.Nat Immunol. 2011; 12: 742-751
- ATF6 mediates a pro-inflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia-reperfusion injury.Am J Transplant. 2014; 14: 1552-1561
- Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.J Immunol. 2014; 192: 5343-5353
- GSK3β and the control of infectious bacterial diseases.Trends Microbiol. 2014; 22: 208-217
- Glycogen synthase kinase-3 represses cyclic AMP response element-binding protein (CREB)-targeted immediate early genes in quiescent cells.J Biol Chem. 2007; 282: 9482-9491
- Toll-like receptor signaling in cell proliferation and survival.Cytokine. 2010; 49: 1-9
- Small heterodimer partner and innate immune regulation.Endocrinol Metab. 2016; 31: 17-24
- Nuclear receptor small heterodimer partner in apoptosis signaling and liver cancer.Cancers. 2011; 3: 198-212
- Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.Science. 2008; 320: 667-670
- GSK-3: functional insights from cell biology and animal models.Front Mol Neurosci. 2011; 4: 40
- Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases.Pharmacol Ther. 2015; 148: 114-131
Published online: February 13, 2018
Accepted: January 30, 2018
Received in revised form: January 8, 2018
Received: September 26, 2017
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.