한빛사 논문
Wonhyo Seo1, Hyuk Soo Eun2,3, So Yeon Kim1, Hyon-Seung Yi3, Young-Sun Lee4, Seol-Hee Park2,5, Mi-Jin Jang6, Eun Jung Jo2, Sun Chang Kim6,7, Yong-Mahn Han6, Keun-Gyu Park8 and Won-Il Jeong1,2,*
1 Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea
2 Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
3 Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
4 Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
5 Department of Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
6 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
7 Intelligent Synthetic Biology Center, Daejeon, Republic of Korea
8 Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
*Contact information: Won-Il Jeong, DVM, Ph.D, Laboratory of Liver Research, Bldg E7 Rm8107, GSMSE/KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Kore
Abstract
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 are not yet fully understood in liver fibrosis. Following acute liver injury and early-stage liver fibrosis induced by a single or 2-week injection of carbon tetrachloride (CCl4), increased interleukin-17A (IL-17A) production was mainly detected 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 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 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.
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. This article is protected by copyright. All rights reserved.
Keywords : RNA; self-ligand; IL-1β; IL-23;R ORγt
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