Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice

Abstract

Innate immune signaling associated with Toll like receptors (TLRs) is a key pathway involved in the progression of nonalcoholic steatohepatitis (NASH). Here we show that both TLR2 and palmitic acid are required for activation of the inflammasome, IL-1α and IL-1β, resulting in the progression of NASH. Wild type (WT) and TLR2−/− mice were fed a choline deficient amino acid defined (CDAA) diet for 22 weeks to induce NASH. Bone marrow transplanted-TLR2 chimeric mice were generated after the recipient mice were lethally irradiated. Kupffer cells and hepatic stellate cells (HSCs) were isolated from WT mice and stimulated with TLR2 ligand and/or palmitic acid. WT mice on the CDAA diet developed profound steatohepatitis and liver fibrosis. In contrast, TLR2−/− mice had suppressed progression of NASH. While both Kupffer cells and HSCs respond to TLR2 ligand, TLR2 bone marrow chimeric mice demonstrated that Kupffer cells were relatively more important than HSCs in TLR2-mediated progression of NASH. In vitro, palmitic acid alone did not increase TLR2 signaling-target genes including cytokines and inflammasome components in Kupffer cells and HSCs. The TLR2 ligand increased Nod-like receptor protein 3, an inflammasome component, in Kupffer cells, but not in HSCs. In the presence of TLR2 ligand, palmitic acid did induce caspase-1 activation and release of IL-1α and IL-1β in Kupffer cells, however, these effects were not observed in HSCs. In vivo, WT on the CDAA diet showed increased caspase-1 activation in the liver and elevated serum levels of IL-1α and IL-1β levels, which were suppressed in TLR2−/− mice. Conclusion: TLR2 and palmitic acid cooperatively activate inflammasome in Kupffer cells/macrophages in the development of NASH.

Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

“…At the same time, TLR2 activation can be triggered by hepatic lipid accumulation (Miura et al 2013). Upon activation, TLR2, TLR4, and TLR9 signal through the MyD88 pathway, activate NF-kb, and result in the production of proinflammatory cytokines and chronic inflammation (Miura et al 2013, Roh & Seki 2013.…”

Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice

“…To this end, we reconstituted hematopoietic cells by generating chimeric mice, in which BM cells lacking TLR were transplanted after the administration of lethal irradiation combined with the depletion of resident macrophages (9,24). Transplanting Tlr4 Ϫ/Ϫ BM cells resulted in the suppression of inflammatory cell infiltration in the Pten ⌬hep mice compared with that observed in the control BM or Tlr2 Ϫ/Ϫ BM cells (Fig.…”

“…⌬hep Mice-Of the various hematopoietic cells expressing TLR4, we focused on macrophages because these cells are a major source of proinflammatory cytokines, which promote the progression of steatohepatitis (21,24). Ly6C is a marker for inflammatory macrophages derived from the BM (25).…”

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice.

“…Lipid-derived products (e.g., free fatty acids and cholesterol) themselves are endogenous DAMPs, and directly activate the inflammasome via both TLR and NLR pathways (13,14). A recent study also demonstrates that ER stress also enhances inflammasome activity through CHOP (41).…”

“…For example, in nonalcoholic fatty liver disease (NAFLD), saturated fatty acids (SFA) but not poly-unsaturated fatty acids (PUFA) have been shown to cause inflammation and cell death (13,14). However, it has also been shown that PUFAs can exacerbate liver injury and markers of inflammation in a murine NAFLD model (15).…”