NLRP3 Inflammasome Activation in Myeloid Cells Is Crucial for Liver Inflammation and Fibrosis in Murine Steatohepatitis

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) is showing a rapidly rising prevalence and meanwhile the leading cause of chronic liver disease worldwide. Inflammation, cellular death, and liver fibrosis are characteristics of the pathogenesis of NAFLD. The NLRP3 inflammasome, a multiprotein complex promoting activation of caspase-1 as well as interleukin 1β (IL-1β) release, is recognized as a key driver of these characteristics. However, the cell-specific contribution of the activation of the NLRP3 inflammasome in NAFLD remains unknown. Method: A conditional Nlrp3 knock-out mouse was generated and bred to mice expressing Cre under the control of Lysozym to investigate the role of NLRP3 inflammasome activation in myeloid cells. Both acute (lipopolysaccharide (LPS)/adenosine-triphosphate (ATP)) and chronic (choline-deficient, L-amino acid-defined high-fat diet (CDAA-HFAT)) liver injury models were used to induce in vivo NLRP3 activation and fibrotic-non-alcoholic steatohepatitis (NASH). Liver inflammation and fibrosis were analysed. Results: Myeloid-specific Nlrp3 knock-out resulted in a systemic and hepatic increase of IL-1β release induced by LPS/ATP injection. NASH-associated hepatic inflammation in the CDAA-HFAT model was ameliorated in myeloid-specific Nlrp3 knock-out mice. Furthermore, myeloid-specific Nlrp3 knock-out mice showed reduced liver fibrosis and decreased hepatic stellate cell activation. Conclusion: This study provides new insights in the cell-specific role of NLRP3 in the pathogenesis of NAFLD. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic-NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of NAFLD.