Exosome-Mediated Activation of Toll-Like Receptor 3 in Stellate Cells Stimulates Interleukin-17 Production by gamma delta T Cells in Liver Fibrosis
- 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
- Issue Date
- Aug-2016
- Publisher
- WILEY-BLACKWELL
- Citation
- HEPATOLOGY, v.64, no.2, pp 616 - 631
- Pages
- 16
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- HEPATOLOGY
- Volume
- 64
- Number
- 2
- Start Page
- 616
- End Page
- 631
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/6220
- DOI
- 10.1002/hep.28644
- ISSN
- 0270-9139
1527-3350
- 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 gamma delta T cells in wild-type (WT) mice. However, liver fibrosis and IL-17A production by gamma delta T cells were both significantly attenuated in TLR3 knockout (KO) mice compared with WT mice. More interestingly, IL-17A-producing gamma delta T cells were in close contact with activated hepatic stellate cells (HSCs), suggesting a role for HSCs in IL-17A production by gamma delta T cells. In vitro treatments with exosomes derived from CCl4-treated hepatocytes significantly increased the expression of IL-17A, IL-1 beta, and IL-23 in WT HSCs but not in TLR3 KO HSCs. Furthermore, IL-17A production by gamma delta 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 gamma delta 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 gamma delta 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 gamma delta 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.
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Collections - 2. Clinical Science > Department of Gastroenterology and Hepatology > 1. Journal Articles
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