3.1.2. TLR3

The protective and anti-inflammatory role of TLR3 has been reported in mice fed with high-fat diet (HFD) followed by binge drinking to induce liver injury. Stimulating TLR3 using poly I:C resulted in elevated HSC and KC IL-10 expression, as well as reduced hepatic expression of TNF-α, IL-6, CXCL2 and impaired liver injury [113].

TLR3 signaling is well characterized in murine natural killer (NK) cells, where activation of TLR3 results in a potent anti-fibrotic effect in both 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-dietand CCl4-induced murine fibrosis models [153,154]. TLR3 has been shown to work synergistically with IL-18 to activate the p38/PI3K/Akt pathway, thus stimulating NK cells to kill HSCs via TNF-related apoptosis-inducing ligand (TRAIL)-mediated degranulation [114]. In contrast, TLR3 is pro-fibrotic in the CCL4 fibrosis model, where TLR3 KO results in downregulation of IL-6, TNF-α, and pro-fibrotic markers [115]. Interestingly, the authors concluded that CCL4-treated hepatocyte exosomes stimulated HSC TLR3 signaling to drive γδ T cell IL-17 production and fibrosis progression [115].
