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NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice
Open accessAbstract
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 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks 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 24weeks, 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.
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“Inflammasome activation is a hallmark of MASH livers (42)”
From Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2 (2024) · cites this paper as [42]
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“Similarly, while inhibition of inflammasome signaling, particularly NLRP3 activation in myeloid cells, demonstrated promising anti-fibrotic effects in murine models (142–144)”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [143]
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“Either in patients with NASH or animal models, the expression of inflammasome components was increased, indicating the potential role in the pathogenesis of liver injury [226,227,288,289,290,291].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [288]
In the citing paper
“Blockade of NLRP3 signaling with a small molecule inhibitor reduces disease severity in the MCD – Foz/Foz murine NASH model, although the relative contributions of targeting other inflammasome-expressing populations, including myeloid cells, have not been determined (77).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [77]
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Cites
Schroder, K., & Tschopp, J. (2010) · Cell · doi:10.1016/j.cell.2010.01.040 · Cited by 5,475
Self-citationNLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Duewell, P., Kono, H., Rayner, K. J., Sirois, C. M., Vladimer, G., Bauernfeind, F. G., Abela, G. S., Franchi, L., Nuñez, G., Schnurr, M., et al. (2010) · Nature · doi:10.1038/nature08938 · Cited by 4,026
Angulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.043 · Cited by 2,987
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Coll, R. C., Robertson, A. A. B., Chae, J. J., Higgins, S. C., Muñoz-Planillo, R., Inserra, M. C., Vetter, I., Dungan, L. S., Monks, B. G., Stutz, A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3806 · Cited by 2,849
Self-citationInflammasome-mediated dysbiosis regulates progression of NAFLD and obesity
Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., et al. (2012) · Nature · doi:10.1038/nature10809 · Cited by 2,435
A lipidomic analysis of nonalcoholic fatty liver disease
Puri, P., Baillie, R. A., Wiest, M. M., Mirshahi, F., Choudhury, J., Cheung, O., Sargeant, C., Contos, M. J., & Sanyal, A. J. (2007) · Hepatology · doi:10.1002/hep.21763 · Cited by 1,338
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Rajamäki, K., Lappalainen, J., Öörni, K., Välimäki, E., Matikainen, S., Kovanen, P. T., & Eklund, K. K. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011765 · Cited by 1,039
Wree, A., Eguchi, A., McGeough, M. D., Pena, C. A., Johnson, C. D., Canbay, A., Hoffman, H. M., & Feldstein, A. E. (2014) · Hepatology · doi:10.1002/hep.26592 · Cited by 945
Self-citationCusi, K. J. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.02.003 · Cited by 940
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The NLRP3 inflammasome: molecular activation and regulation to therapeutics
Swanson, K. V., Deng, M., & Ting, J. P.-Y. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0165-0 · Cited by 4,884
Mechanisms of NAFLD development and therapeutic strategies
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018) · Nature Medicine · doi:10.1038/s41591-018-0104-9 · Cited by 4,354
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002
Molecular and cellular mechanisms of liver fibrosis and its regression
Kisseleva, T., & Brenner, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00372-7 · Cited by 2,024
Targeting the NLRP3 inflammasome in inflammatory diseases
Mangan, M. S. J., Olhava, E. J., Roush, W. R., Seidel, H. M., Glick, G. D., & Latz, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.97 · Cited by 1,885
Metadata
- Authors
- Mridha, A. R., Wree, A., Robertson, A. A. B., Yeh, M. M., Johnson, C. D., Van Rooyen, D. M., Haczeyni, F., Teoh, N. C.-H., Savard, C., Ioannou, G. N., Masters, S. L., Schroder, K., Cooper, M. A., Feldstein, A. E., & Farrell, G. C.
- Affiliations
- Australian National University (AU)
- University of California San Diego (US)
- The University of Queensland (AU)
- University of Washington (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Farrell, Geoffrey C.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 66
- Issue
- 5
- Pages
- 1037-1046
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC6536116
- OpenAlex
- W2585046292
- Cited by
- 1,110
- References
- 49
- Citations by year
- 2026: 117 · 2025: 147 · 2024: 126 · 2023: 150 · 2022: 160 · 2021: 143 · 2020: 121 · 2019: 61 · 2018: 70 · 2017: 14
- FWCI
- 57.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ANU Open Research (Australian National University) (submittedVersion, cc-by-nc-nd)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (U01AA022489, R21AA023574)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113592)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- NLRP3 inflammasome, MCC950, nonalcoholic steatohepatitis, liver fibrosis, liver inflammation, IL-1β, caspase-1, cholesterol crystals, Kupffer cells, macrophages, neutrophil migration, methionine-choline-deficient diet, atherogenic diet, myeloid cells
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Female, Furans, Hepatitis, Heterocyclic Compounds, 4 or More Rings, Indenes, Liver Cirrhosis, Experimental, Sulfonamides, Sulfones, NF-kappa B, Reactive Oxygen Species, Mice, Interleukin-1beta, Non-alcoholic Fatty Liver Disease
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