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,
interleukin (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. Although 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 mice 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: