title: Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis.
abstract: 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.
  
  
  
  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).
authors.affiliation: Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea.
authors.forename: Wonhyo
authors.initials: W
authors.lastname: Seo
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.|Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Hyuk Soo
authors.initials: HS
authors.lastname: Eun
authors.affiliation: Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.|Department of Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Jang
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.|Intelligent Synthetic Biology Center, Daejeon, Republic of Korea.
authors.forename: Sun Chang
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Yong-Mahn
authors.initials: YM
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea.|Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D055354:Exosomes; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016692:Receptors, Antigen, T-Cell, gamma-delta; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3