Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice.

The importance of toll-like receptor (TLR) 4 has been well documented in pathogenesis of steatohepatitis, however, little is known about the role of TLR3. In this study, we investigated whether the depletion of TLR3 modulate the hepatic injury in mice, and further try to provide mechanistic insight of TLR3-mediated modulation from diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were developed by feeding wild type (WT) or TLR3 knockout mice with high-fat diet for 8 weeks. Primary liver resident cells including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs) were treated with palmitic acid. TLR3 knockout mice fed high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-κB and IRF3 activation which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells of TLR3 knockout mice compared to the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis.