Abstract
Interleukin (IL)-33 has been recently reported to be strongly pro-fibrogenic in various models of liver disease. Our aim was to study the role of endogenous IL-33 in a diet-induced model of steatohepatitis. IL-33 deficient mice and wild type (WT) littermates received a high-fat diet (HFD), or a standard diet for 12 weeks. The HFD-induced steatohepatitis was associated with an upregulation of IL-33 transcripts and protein. An insulin tolerance test revealed lower systemic insulin sensitivity in IL-33-/—HFD mice than in WT-HFD mice. Nevertheless, IL-33 deficiency did not affect the severity of liver inflammation by histological and transcriptomic analyses, nor the quantity of liver fibrosis. Livers from HFD mice had more myeloid populations, markedly fewer NKT cells and higher proportion of ST2+ Treg cells and ST2+ type 2 innate lymphoid cells (ILC2), all unaffected by IL-33 deficiency. In conclusion, deficiency of endogenous IL-33 does not affect the evolution of experimental diet-induced steatohepatitis towards liver fibrosis.
Highlights
Nonalcoholic Fatty Liver Disease (NAFLD) is a significant cause of mortality due to liver-related complications, i.e. cirrhosis and hepatocellular carcinoma, and its extrahepatic manifestations, such as cardiovascular diseases [1]
Among all cytokines involved in liver fibrogenesis, we have shown that interleukin (IL)-33 hepatic expression is upregulated in cirrhotic patients and www.impactjournals.com/oncotarget in a toxic model of liver fibrosis [6], and sustained release of IL-33 from liver cells has been shown to promote severe fibrosis in mice [7]
IL-33 is pro-fibrogenic, as its hepatic expression is sufficient to drive severe liver fibrosis through ILC2derived IL-13; which is further demonstrated by a strong reduction of experimentally-induced liver fibrosis in mice lacking IL-33 [7]
Summary
Nonalcoholic Fatty Liver Disease (NAFLD) is a significant cause of mortality due to liver-related complications, i.e. cirrhosis and hepatocellular carcinoma, and its extrahepatic manifestations, such as cardiovascular diseases [1]. Nonalcoholic steatohepatitis (NASH) develops in response to inflammatory stimuli, such as lipotoxicity or bacterial translocation, leading to cell death and fibrosis [2]. Among all cytokines involved in liver fibrogenesis, we have shown that interleukin (IL)-33 hepatic expression is upregulated in cirrhotic patients and www.impactjournals.com/oncotarget in a toxic model of liver fibrosis [6], and sustained release of IL-33 from liver cells has been shown to promote severe fibrosis in mice [7]. Gao et al demonstrated that administration of recombinant exogenous IL-33 aggravates liver fibrosis during experimental NAFLD [15]. This prompted us to study the implication of endogenous IL-33 during experimental NAFLD. We used a diet-induced model of steatohepatitis, where mice are not obese and do not display features of metabolic syndrome, to focus on the implication of IL-33 in liver pathology and bypass indirect activity on metabolic parameters [17, 18]
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