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

Mridha, Auvro R., Wree, Alexander, Robertson, Avril A. B., Yeh, Matthew M., Johnson, Casey D., Van Rooyen, Derrick M., Haczeyni, Fahrettin, Teoh, Narci C. -H., Savard, Christopher, Ioannou, George N., Masters, Seth L., Schroder, Kate, Cooper, Matthew A., Feldstein, Ariel E. and Farrell, Geoffrey C. (2017) NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. Journal of Hepatology, 66 5: 1037-1046. doi:10.1016/j.jhep.2017.01.022


Author Mridha, Auvro R.
Wree, Alexander
Robertson, Avril A. B.
Yeh, Matthew M.
Johnson, Casey D.
Van Rooyen, Derrick M.
Haczeyni, Fahrettin
Teoh, Narci C. -H.
Savard, Christopher
Ioannou, George N.
Masters, Seth L.
Schroder, Kate
Cooper, Matthew A.
Feldstein, Ariel E.
Farrell, Geoffrey C.
Title NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice
Journal name Journal of Hepatology   Check publisher's open access policy
ISSN 1600-0641
0168-8278
Publication date 2017-05-01
Sub-type Article (original research)
DOI 10.1016/j.jhep.2017.01.022
Open Access Status Not yet assessed
Volume 66
Issue 5
Start page 1037
End page 1046
Total pages 10
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Formatted 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.

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.
Keyword Cholesterol crystals
Diet, atherogenic
Fibrosis
Hepatocytes
Inflammasomes
Interleukin-1β
Kupffer cells
Methionine
NAFLD
NLR proteins
NLRP3
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 08 May 2017, 01:00:44 EST by Web Cron on behalf of Learning and Research Services (UQ Library)