(The) role of exosome-mediated activation of toll-like receptor 3 in hepatic stellate cells during liver fibrogenesis간섬유화 과정에서 exosome 매개 toll-like receptor 3 활성화를 통한 간성상세포의 역할에 관한 연구
During liver injury, damaged hepatocytes are able to release exosomes that include diverse types of self-RNAs. Recently, self-noncoding RNA has been recognized as an activator of Toll-like receptor 3 (TLR3). However, the roles of hepatocyte-derived exosomes and the activation of TLR3 are not yet fully understood in the pathogenesis of liver fibrosis. Following acute liver injury and early-stage liver fibrosis induced by a single or 2-week injection of carbon tetrachloride $(CCl_4)$, increased interleukin-17A (IL-17A) production was mainly detected in hepatic γδ T cells in wild-type (WT) mice. However, the degree of liver fibrosis and IL-17A production by γδ T cells were both significantly attenuated in TLR3 KO mice compared with WT mice. More interestingly, IL-17A-producing γδ T cells were in close contact with activated hepatic stellate cells (HSCs), suggesting an interaction between HSCs and γδ T cells. In vitro treatments with exosomes derived from $CCl_4-treated$ hepatocytes significantly increased the expression of IL-17A, IL-1β, and IL-23 in WT HSCs but not in TLR3 KO HSCs. Furthermore, IL-17A production by γδ T cells was substantially increased upon co-culturing with exosome-treated WT HSCs or conditioned medium from TLR3-activated WT HSCs. However, similar increases were not detected when γδ T cells were co-cultured with exosome-treated HSCs from IL-17A KO or TLR3 KO mice. Using reciprocal bone marrow transplantation between WT and TLR3 KO mice, we demonstrated that TLR3 deficiency in HSCs contributed to decreased IL-17A production by γδ T cells, as well as liver fibrosis. In liver injury, the exosome-mediated activation of TLR3 in HSCs exacerbates liver fibrosis by enhancing IL-17A production by γδ T cells, which might be associated with HSC stimulation by unknown self-TLR3 ligands from damaged hepatocytes. Therefore, TLR3 might be a novel therapeutic target for liver fibrosis.