NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice

By Auvro R. Mridha, A. Wree, A. Robertson, M. Yeh, Casey D. Johnson, Derrick M. Van Rooyen, F. Haczeyni, Narci C. Teoh, Christopher Savard, G. Ioannou and 5 more. Journal of Hepatology, 2017

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Background & Aims: NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis. Methods: We fed foz/foz and wild-type mice an atherogenic diet for 16 weeks, gavaged MCC950 or vehicle until 24 weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6 weeks and determined the effects on liver fibrosis. Results: In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24 weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis. Conclusion: MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH. Lay summary: Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis.

Subfields: Epidemiology, Hepatology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0a555872198ff7b12f7d462cfd9c49dcd4273332

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Citations in the corpus

Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, background): “However, while some studies confirmed that the lack of inflammasome components might protect against the development of liver injury in experimental models of NAFLD, others have shown that their absence is associated with a more aggressive disease [96-100].”
MASLD: a systemic metabolic disorder with cardiovascular and malignant complications (2024, background): “40 41 Chronic liver inflammation is a major driver of liver fibrosis and further complications of MASLD, both inside and outside of the liver.”
Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease (2018, background): “Several evidences in literature demonstrated that the inflammasome activity drives NASH progression, and the inhibition of its activation may improve NAFLD pathology and fibrosis [87, 88].”
Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “Therefore, blockade of NLRP3 pathway emerges as a novel therapeutic target to reduce liver inflammation and fibrosis in NASH [168].”
Mechanisms and disease consequences of nonalcoholic fatty liver disease (2021, background): “Among the different types of inflammasomes, the NLRP3 complex has been characterized most extensively in NASH, and its inhibition in myeloid cells attenuates inflammation and fibrosis in a rodent model (Mridha et al., 2017).”