Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

Alexander Wree; Theresa Maria Holtmann; Maria Eugenia Inzaugarat; Ariel E. Feldstein

doi:10.1055/s-0039-1685515

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2019; 39(03): 275-282
DOI: 10.1055/s-0039-1685515

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

Alexander Wree

¹Department of Hepatology and Gastroenterology, Charité Campus Mitte and Campus Virchow Clinic, Charité University Medicine, Berlin, Germany

²Department of Pediatric Gastroenterology, University of California, San Diego (UCSD), San Diego, California and Rady Children's Hospital, San Diego, California

,

Theresa Maria Holtmann

³Department of Internal Medicine III, Aachen University Hospital, RWTH Aachen, Aachen, Germany

,

Maria Eugenia Inzaugarat

³Department of Internal Medicine III, Aachen University Hospital, RWTH Aachen, Aachen, Germany

,

Ariel E. Feldstein

²Department of Pediatric Gastroenterology, University of California, San Diego (UCSD), San Diego, California and Rady Children's Hospital, San Diego, California

› Author Affiliations

Abstract

Hepatocyte demise as well as signals released by stressed hepatocytes have been now recognized as important triggers of liver inflammation. While traditional concepts classically viewed hepatocyte cell death to occur by either a nonlytic, noninflammatory form (apoptosis), or lytic, proinflammatory nonregulated cell death (necrosis), recent studies have provided evidence for additional mechanisms that can contribute to both acute and chronic liver damage. Two novel forms of cell death, pyroptosis and necroptosis, are of particular importance as they are highly regulated and intrinsically proinflammatory. Additionally, stressed hepatocytes may also release signals to attract and activate monocytes into proinflammatory macrophages. In this review, the authors discuss recent developments supporting the role of novel triggers of liver inflammation in various forms of liver injury and their potential translational implications.

Keywords

cell death - pyroptosis - necroptosis - liver injury - liver fibrosis

Full Text

References

References
1 Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol 2018; 15 (06) 349-364
2 Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13 (03) 267-276
3 Wree A, Mehal WZ, Feldstein AE. Targeting cell death and sterile inflammation loop for the treatment of nonalcoholic steatohepatitis. Semin Liver Dis 2016; 36 (01) 27-36
4 Eguchi A, Wree A, Feldstein AE. Biomarkers of liver cell death. J Hepatol 2014; 60 (05) 1063-1074
5 Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 2018; 67 (05) 963-972
6 Brennan MA, Cookson BT. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 2000; 38 (01) 31-40
7 de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ 2018 Doi: 10.1038/s41418-018-0106-7
8 Alegre F, Pelegrin P, Feldstein AE. Inflammasomes in liver fibrosis. Semin Liver Dis 2017; 37 (02) 119-127
9 Galluzzi L, Vitale I, Abrams JM. , et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012; 19 (01) 107-120
10 Liu X, Zhang Z, Ruan J. , et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016; 535 (7610): 153-158
11 Kayagaki N, Stowe IB, Lee BL. , et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015; 526 (7575): 666-671
12 Galluzzi L, Vitale I, Aaronson SA. , et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018; 25 (03) 486-541
13 Aachoui Y, Sagulenko V, Miao EA, Stacey KJ. Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Curr Opin Microbiol 2013; 16 (03) 319-326
14 Wang Y, Gao W, Shi X. , et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 2017; 547 (7661): 99-103
15 Ding J, Wang K, Liu W. , et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016; 535 (7610): 111-116
16 Baroja-Mazo A, Martín-Sánchez F, Gomez AI. , et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 2014; 15 (08) 738-748
17 Franklin BS, Bossaller L, De Nardo D. , et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol 2014; 15 (08) 727-737
18 Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 627-636
19 Luan J, Zhang X, Wang S. , et al. NOD-like receptor protein 3 inflammasome-dependent IL-1β accelerated ConA-induced hepatitis. Front Immunol 2018; 9: 758
20 Heo MJ, Kim TH, You JS, Blaya D, Sancho-Bru P, Kim SG. Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression. Gut 2018; gutjnl-2017-315123 . Doi: 10.1136/gutjnl-2017-315123
21 Peeters PM, Wouters EF, Reynaert NL. Immune homeostasis in epithelial cells: evidence and role of inflammasome signaling reviewed. J Immunol Res 2015; 2015: 828264
22 Santana PT, Martel J, Lai HC. , et al. Is the inflammasome relevant for epithelial cell function?. Microbes Infect 2016; 18 (02) 93-101
23 Wree A, Eguchi A, McGeough MD. , et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 2014; 59 (03) 898-910
24 Chen YL, Xu G, Liang X. , et al. Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury. Am J Transl Res 2016; 8 (12) 5685-5695
25 Heymann F, Hamesch K, Weiskirchen R, Tacke F. The concanavalin A model of acute hepatitis in mice. Lab Anim 2015; 49 (1, Suppl): 12-20
26 Bonder CS, Ajuebor MN, Zbytnuik LD, Kubes P, Swain MG. Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis. J Immunol 2004; 172 (01) 45-53
27 Trautwein C, Rakemann T, Brenner DA. , et al. Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastroenterology 1998; 114 (05) 1035-1045
28 Kato J, Okamoto T, Motoyama H. , et al. Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. Hepatology 2013; 57 (01) 362-372
29 Künstle G, Hentze H, Germann PG, Tiegs G, Meergans T, Wendel A. Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. Hepatology 1999; 30 (05) 1241-1251
30 Kofahi HM, Taylor NG, Hirasawa K, Grant MD, Russell RS. Hepatitis C virus infection of cultured human hepatoma cells causes apoptosis and pyroptosis in both infected and bystander cells. Sci Rep 2016; 6: 37433
31 Xu B, Jiang M, Chu Y. , et al. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2017; ; pii: S0168-8278(17)32494-7 . Doi: 10.1016/j.jhep.2017.11.040
32 Khanova E, Wu R, Wang W. , et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 2018; 67 (05) 1737-1753
33 Vercammen D, Beyaert R, Denecker G. , et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 1998; 187 (09) 1477-1485
34 Degterev A, Huang Z, Boyce M. , et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005; 1 (02) 112-119
35 Meylan E, Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 2005; 30 (03) 151-159
36 Gong YN, Guy C, Crawford JC, Green DR. Biological events and molecular signaling following MLKL activation during necroptosis. Cell Cycle 2017; 16 (19) 1748-1760
37 Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 2013; 38 (02) 209-223
38 Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61 (03) 1066-1079
39 Sun B, Karin M. Inflammation and liver tumorigenesis. Front Med 2013; 7 (02) 242-254
40 Boege Y, Malehmir M, Healy ME. , et al. A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell 2017; 32 (03) 342-359.e10
41 Panayotova-Dimitrova D, Feoktistova M, Ploesser M. , et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Reports 2013; 5 (02) 397-408
42 Vanden Berghe T, Grootjans S, Goossens V. , et al. Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods 2013; 61 (02) 117-129
43 Sun L, Wang H, Wang Z. , et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012; 148 (1-2): 213-227
44 Dara L, Liu ZX, Kaplowitz N. Questions and controversies: the role of necroptosis in liver disease. Cell Death Discov 2016; 2: 16089
45 Dara L, Johnson H, Suda J. , et al. Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis. Hepatology 2015; 62 (06) 1847-1857
46 Günther C, He GW, Kremer AE. , et al. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J Clin Invest 2016; 126 (11) 4346-4360
47 Degterev A, Zhou W, Maki JL, Yuan J. Assays for necroptosis and activity of RIP kinases. Methods Enzymol 2014; 545: 1-33
48 Krenkel O, Mossanen JC, Tacke F. Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg Nutr 2014; 3 (06) 331-343
49 Takemoto K, Hatano E, Iwaisako K. , et al. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio 2014; 4: 777-787
50 Deutsch M, Graffeo CS, Rokosh R. , et al. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis 2015; 6: e1759
51 Li JX, Feng JM, Wang Y. , et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis 2014; 5: e1278
52 Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX, Jaeschke H. Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 2013; 58 (06) 2099-2108
53 Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. Chem Res Toxicol 2011; 24 (06) 794-796
54 Zhou Y, Dai W, Lin C. , et al. Protective effects of necrostatin-1 against concanavalin A-induced acute hepatic injury in mice. Mediators Inflamm 2013; 2013: 706156
55 Arshad MI, Piquet-Pellorce C, Filliol A. , et al. The chemical inhibitors of cellular death, PJ34 and Necrostatin-1, down-regulate IL-33 expression in liver. J Mol Med (Berl) 2015; 93 (08) 867-878
56 Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C. , et al. TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ 2012; 19 (12) 2003-2014
57 Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 2013; 57 (05) 1773-1783
58 Wang S, Ni HM, Dorko K. , et al. Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury. Oncotarget 2016; 7 (14) 17681-17698
59 Gautheron J, Vucur M, Reisinger F. , et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol Med 2014; 6 (08) 1062-1074
60 Roychowdhury S, McCullough RL, Sanz-Garcia C. , et al. Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 2016; 64 (05) 1518-1533
61 Afonso MB, Rodrigues PM, Carvalho T. , et al. Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clin Sci (Lond) 2015; 129 (08) 721-739
62 Moriwaki K, Chan FK. Necroptosis-independent signaling by the RIP kinases in inflammation. Cell Mol Life Sci 2016; 73 (11-12): 2325-2334
63 Moriwaki K, Bertin J, Gough PJ, Chan FK. A RIPK3-caspase 8 complex mediates atypical pro-IL-1β processing. J Immunol 2015; 194 (04) 1938-1944
64 Lawlor KE, Khan N, Mildenhall A. , et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun 2015; 6: 6282
65 Dara L. The receptor interacting protein kinases in the liver. Semin Liver Dis 2018; 38 (01) 73-86
66 Povero D, Eguchi A, Niesman IR. , et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal 2013; 6 (296) ra88
67 Povero D, Panera N, Eguchi A. , et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol 2015; 1 (06) 646-663.e4
68 Szabo G, Momen-Heravi F. Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat Rev Gastroenterol Hepatol 2017; 14 (08) 455-466
69 Ibrahim SH, Hirsova P, Tomita K. , et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 2016; 63 (03) 731-744
70 Cannito S, Morello E, Bocca C. , et al. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PLoS One 2017; 12 (03) e0172575
71 Hirsova P, Ibrahim SH, Krishnan A. , et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 2016; 150 (04) 956-967
72 Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 2016; 57 (02) 233-245
73 Garcia-Martinez I, Santoro N, Chen Y. , et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 2016; 126 (03) 859-864
74 Cai Y, Xu MJ, Koritzinsky EH. , et al. Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity. JCI Insight 2017; 2 (14) 2
75 Verma VK, Li H, Wang R. , et al. Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol 2016; 64 (03) 651-660
76 Momen-Heravi F, Bala S, Kodys K, Szabo G. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep 2015; 5: 9991