Exosome‐mediated activation of toll‐like receptor 3 in stellate cells stimulates interleukin‐17 production by γδ T cells in liver fibrosis

• Published in: Hepatology (Baltimore, Md.) Vol. 64; no. 2; pp. 616 - 631
• Main Authors: Seo, Wonhyo, Eun, Hyuk Soo, Kim, So Yeon, Yi, Hyon‐Seung, Lee, Young‐Sun, Park, Seol‐Hee, Jang, Mi‐Jin, Jo, Eunjung, Kim, Sun Chang, Han, Yong‐Mahn, Park, Keun‐Gyu, Jeong, Won‐Il
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2016
• Subjects: Animals; Bone marrow transplantation; Carbon tetrachloride; Carbon Tetrachloride Poisoning - metabolism; Cytokines; Exosomes; Fibrosis; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatology; Interleukin-17 - metabolism; Liver; Liver Cirrhosis - metabolism; Lymphocytes; Lymphocytes T; Male; Mice, Inbred C57BL; Mice, Transgenic; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Stellate cells; T-Lymphocytes - metabolism; Therapeutic targets; TLR3 protein; Toll-Like Receptor 3 - metabolism; Toll-like receptors
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.28644

During liver injury, hepatocytes secrete 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 hepatic exosomes and TLR3 in liver fibrosis are not yet fully understood. Following acute liver injury and early‐stage liver fibrosis induced by a single or 2‐week injection of carbon tetrachloride (CCl4), increased interleukin (IL)‐17A production was detected primarily in hepatic γδ T cells in wild‐type (WT) mice. However, liver fibrosis and IL‐17A production by γδ T cells were both significantly attenuated in TLR3 knockout (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 a role for HSCs in IL‐17A production by γδ T cells. In vitro treatments with exosomes derived from CCl4‐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 coculturing with exosome‐treated WT HSCs or conditioned medium from TLR3‐activated WT HSCs. However, similar increases were not detected when γδ T cells were cocultured with exosome‐treated HSCs from IL‐17A KO or TLR3 KO mice. Using reciprocal bone marrow transplantation between WT and TLR3 KO mice, we found that TLR3 deficiency in HSCs contributed to decreased IL‐17A production by γδ T cells, as well as liver fibrosis. Conclusion: 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. (Hepatology 2016;64:616‐631)