NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice
Date
2017-05
Authors
Mridha, Auvro
Wree, Alexander
Robertson, Avril
Yeh, Matthew
Johnson, Casey D.
Van Rooyen, Derrick
Haczeyni, Fahrettin
Teoh, Narcissus
Savard, Christopher
Ioannou, George
Journal Title
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Volume Title
Publisher
Elsevier
Abstract
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.
Description
Keywords
NAFLD, NLRP3, Inflammasomes, Cholesterol crystals, Kupffer cells, Hepatocytes, Interleukin-1b, Fibrosis, Diet, atherogenic, Methionine, NLR proteins
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Source
Journal of Hepatology
Type
Journal article
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Open Access
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CC BY-NC-ND
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Author Accepted Manuscript