The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

Jana Knorr; Alexander Wree; Frank Tacke; Ariel E. Feldstein

doi:10.1055/s-0040-1708540

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2020; 40(03): 298-306
DOI: 10.1055/s-0040-1708540

Review Article

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

Jana Knorr

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

,

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

,

Frank Tacke

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

› Institutsangaben

Abstract

Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (ASH) are advanced forms of fatty liver diseases that are associated with a high morbidity and mortality worldwide. Patients with ASH or NASH are more susceptible to the progression of fibrosis and cirrhosis up to the development of hepatocellular carcinoma. Currently, there are limited medical therapies available. Accompanied by the asymptomatic disease progression, the demand for liver transplants is high. This review provides an overview about the growing evidence for a central role of NLR family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that acts as a central driver of inflammation via activation of caspase 1, maturation and release of pro-inflammatory cytokines including interleukin-1β, and trigger of inflammatory pyroptotic cell death in both NASH and ASH. We also discuss potential therapeutic approaches targeting NLRP3 inflammasome and related upstream and downstream pathways to develop prognostic biomarkers and medical treatments for both liver diseases.

Keywords

NLRP3 - nonalcoholic steatohepatitis - alcoholic steatohepatitis - inflammation - inflammasome

Volltext

Referenzen

References
1 Estes C, Anstee QM, Arias-Loste MT. , et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol 2018; 69 (04) 896-904
2 Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10: 686-690
3 Younossi Z, Tacke F, Arrese M. , et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2019; 69 (06) 2672-2682
4 Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94 (09) 2467-2474
5 O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (01) 307-328
6 Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology 2014; 147 (04) 754-764
7 WHO. Global status report on alcohol and health 2018. 2018 . Available at: https://apps.who.int/iris/bitstream/handle/10665/274603/9789241565639-eng.pdf . Accessed February 4, 2020
8 Dulai PS, Singh S, Patel J. , et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 2017; 65 (05) 1557-1565
9 Perazzo H, Dufour J-F. The therapeutic landscape of non-alcoholic steatohepatitis. Liver Int 2017; 37 (05) 634-647
10 Lassailly G, Caiazzo R, Pattou F, Mathurin P. Perspectives on treatment for nonalcoholic steatohepatitis. Gastroenterology 2016; 150 (08) 1835-1848
11 Reimer KC, Wree A, Roderburg C, Tacke F. New drugs for NAFLD: lessons from basic models to the clinic. Hepatol Int 2019
12 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L. , et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149 (02) 367.e5-378.e5 , quiz e14–e15
13 Cholankeril G, Ahmed A. Alcoholic liver disease replaces hepatitis C virus infection as the leading indication for liver transplantation in the United States. Clin Gastroenterol Hepatol 2018; 16 (08) 1356-1358
14 Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 2019; 70 (02) 249-259
15 Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate immunity and inflammation in NAFLD/NASH. Dig Dis Sci 2016; 61 (05) 1294-1303
16 Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332 (6037): 1519-1523
17 Próchnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000 Res 2016; 5: 5
18 Guarda G, Zenger M, Yazdi AS. , et al. Differential expression of NLRP3 among hematopoietic cells. J Immunol 2011; 186 (04) 2529-2534
19 Yazdi AS, Drexler SK, Tschopp J. The role of the inflammasome in nonmyeloid cells. J Clin Immunol 2010; 30 (05) 623-627
20 Booshehri LM, Hoffman HM. CAPS and NLRP3. J Clin Immunol 2019; 39 (03) 277-286
21 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140 (06) 821-832
22 Liu X, Zhang Z, Ruan J. , et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016; 535 (7610): 153-158
23 Kayagaki N, Stowe IB, Lee BL. , et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015; 526 (7575): 666-671
24 Shi J, Zhao Y, Wang K. , et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015; 526 (7575): 660-665
25 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. Hepatology 2011; 54 (01) 133-144
26 Wree A, McGeough MD, Peña CA. , et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl) 2014; 92 (10) 1069-1082
27 Mridha AR, Wree A, Robertson AAB. , et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol 2017; 66 (05) 1037-1046
28 Blasetti Fantauzzi C, Menini S, Iacobini C. , et al. Deficiency of the purinergic receptor 2X₇ attenuates nonalcoholic steatohepatitis induced by high-fat diet: possible role of the NLRP3 inflammasome. Oxid Med Cell Longev 2017; 2017: 8962458
29 Dixon LJ, Berk M, Thapaliya S, Papouchado BG, Feldstein AE. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest 2012; 92 (05) 713-723
30 Dixon LJ, Flask CA, Papouchado BG, Feldstein AE, Nagy LE. Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 2013; 8 (02) e56100
31 Henao-Mejia J, Elinav E, Jin C. , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384): 179-185
32 Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007; 47 (04) 571-579
33 Brun P, Castagliuolo I, Di Leo V. , et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292 (02) G518-G525
34 Nakanishi K, Kaji K, Kitade M. , et al. Exogenous administration of low-dose lipopolysaccharide potentiates liver fibrosis in a choline-deficient l-amino-acid-defined diet-induced murine steatohepatitis model. Int J Mol Sci 2019; 20 (11) 2724
35 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 2018; 68 (04) 773-782
36 Lang S, Duan Y, Liu J. , et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology 2020; 71 (02) 522-538
37 Sarin SK, Pande A, Schnabl B. Microbiome as a therapeutic target in alcohol-related liver disease. J Hepatol 2019; 70 (02) 260-272
38 Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015; 148 (01) 30-36
39 Duan Y, Llorente C, Lang S. , et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575 (7783): 505-511
40 Petrasek J, Bala S, Csak T. , et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012; 122 (10) 3476-3489
41 Petrasek J, Iracheta-Vellve A, Saha B. , et al. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease. J Leukoc Biol 2015; 98 (02) 249-256
42 Iracheta-Vellve A, Petrasek J, Satishchandran A. , et al. Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. J Hepatol 2015; 63 (05) 1147-1155
43 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 2019; 68 (04) 708-720
44 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
45 Machado MV, Michelotti GA, Xie G. , et al. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One 2015; 10 (05) e0127991
46 Pihlajamäki J, Kuulasmaa T, Kaminska D. , et al. Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans. J Hepatol 2012; 56 (03) 663-670
47 He K, Zhu X, Liu Y. , et al. Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease development. Oncotarget 2017; 8 (23) 37657-37672
48 Zhu L, Baker SS, Gill C. , et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (02) 601-609
49 Wong VW-S, Tse C-H, Lam TT-Y. , et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One 2013; 8 (04) e62885
50 Boursier J, Mueller O, Barret M. , et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016; 63 (03) 764-775
51 Grant RW, Dixit VD. Mechanisms of disease: inflammasome activation and the development of type 2 diabetes. Front Immunol 2013; 4: 50
52 Goossens GH, Blaak EE, Theunissen R. , et al. Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Mol Immunol 2012; 50 (03) 142-149
53 Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 2013; 62 (01) 194-204
54 Ohashi K, Pimienta M, Seki E. Alcoholic liver disease: a current molecular and clinical perspective. Liver Res 2018; 2 (04) 161-172
55 Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004; 127 (05) (Suppl. 01) S87-S96
56 Nurmi K, Virkanen J, Rajamäki K, Niemi K, Kovanen PT, Eklund KK. Ethanol inhibits activation of NLRP3 and AIM2 inflammasomes in human macrophages--a novel anti-inflammatory action of alcohol. PLoS One 2013; 8 (11) e78537-e78537
57 Hoyt LR, Ather JL, Randall MJ. , et al. Ethanol and other short-chain alcohols inhibit NLRP3 inflammasome activation through protein tyrosine phosphatase stimulation. J Immunol 2016; 197 (04) 1322-1334
58 Hoyt LR, Randall MJ, Ather JL. , et al. Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome. Redox Biol 2017; 12: 883-896
59 Le Daré B, Victoni T, Bodin A. , et al. Ethanol upregulates the P2 × 7 purinergic receptor in human macrophages. Fundam Clin Pharmacol 2019; 33 (01) 63-74
60 Voican CS, Njiké-Nakseu M, Boujedidi H. , et al. Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver Int 2015; 35 (03) 967-978
61 Peng Y, French BA, Tillman B, Morgan TR, French SW. The inflammasome in alcoholic hepatitis: its relationship with Mallory-Denk body formation. Exp Mol Pathol 2014; 97 (02) 305-313
62 Leclercq S, Matamoros S, Cani PD. , et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 2014; 111 (42) E4485-E4493
63 Mutlu EA, Gillevet PM, Rangwala H. , et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302 (09) G966-G978
64 Szabo G, Mitchell MC, McClain CJ. , et al. IL-1 receptor antagonist in combination with pentoxifylline and zinc for severe alcoholic hepatitis: a multicenter randomized double-bind placebo-controlled clinical trial. Hepatology 2018; 68: 1444A-1471A
65 Thomas MG, Bayliss C, Bond S. , et al. Trial summary and protocol for a phase II randomised placebo-controlled double-blinded trial of Interleukin 1 blockade in Acute Severe Colitis: the IASO trial. BMJ Open 2019; 9 (02) e023765
66 Cohen SB, Proudman S, Kivitz AJ. , et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther 2011; 13 (04) R125
67 Thursz MR, Richardson P, Allison M. , et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372 (17) 1619-1628
68 Naveau S, Chollet-Martin S, Dharancy S. , et al; Foie-Alcool group of the Association Française pour l'Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004; 39 (05) 1390-1397
69 Zein CO, Yerian LM, Gogate P. , et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54 (05) 1610-1619
70 Morrison MC, Mulder P, Salic K. , et al. Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR-/-.Leiden mice. Int J Obes 2016; 40 (09) 1416-1423
71 Stack JH, Beaumont K, Larsen PD. , et al. IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol 2005; 175 (04) 2630-2634
72 Wannamaker W, Davies R, Namchuk M. , et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 2007; 321 (02) 509-516
73 Cabrera D, Wree A, Povero D. , et al. Andrographolide ameliorates inflammation and fibrogenesis and attenuates inflammasome activation in experimental non-alcoholic steatohepatitis. Sci Rep 2017; 7 (01) 3491
74 Coll RC, Robertson AAB, Chae JJ. , et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 2015; 21 (03) 248-255
75 Juliana C, Fernandes-Alnemri T, Wu J. , et al. Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 2010; 285 (13) 9792-9802
76 Honda H, Nagai Y, Matsunaga T. , et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J Leukoc Biol 2014; 96 (06) 1087-1100
77 Calvente CJ, Tameda M, Johnson CD. , et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest 2019; 130: 4091-4109
78 Jimenez Calvente C, Del Pilar H, Tameda M, Johnson CD, Feldstein AE. MicroRNA 223 3p negatively regulates the NLRP3 inflammasome in acute and chronic liver injury. Mol Ther 2019; (e-pub ahead of print)
79 Rathkey JK, Zhao J, Liu Z. , et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol 2018; 3 (26) eaat2738