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

Wonhyo Seo, Hyuk Soo Eun, So Yeon Kim, Hyon Seung Yi, Young-Sun Lee, Seol Hee Park, Mi Jin Jang, Eunjung Jo, Sun Chang Kim, Yong Mahn Han, Keun Gyu Park, Won Il Jeong

Research output: Contribution to journalArticle

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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. 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).

Original languageEnglish
Pages (from-to)616-631
Number of pages16
JournalHepatology
Volume64
Issue number2
DOIs
Publication statusPublished - 2016 Aug 1

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Toll-Like Receptor 3
Exosomes
Hepatic Stellate Cells
Interleukin-17
Liver Cirrhosis
T-Lymphocytes
Hepatocytes
Knockout Mice
Liver
Wounds and Injuries
Interleukin-23
Untranslated RNA
Carbon Tetrachloride
Gastroenterology
Conditioned Culture Medium
Bone Marrow Transplantation
Interleukin-1

ASJC Scopus subject areas

  • Hepatology

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

In: Hepatology, Vol. 64, No. 2, 01.08.2016, p. 616-631.

Research output: Contribution to journalArticle

Seo, W, Eun, HS, Kim, SY, Yi, HS, Lee, Y-S, Park, SH, Jang, MJ, Jo, E, Kim, SC, Han, YM, Park, KG & Jeong, WI 2016, 'Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis', Hepatology, vol. 64, no. 2, pp. 616-631. https://doi.org/10.1002/hep.28644
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. / Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. In: Hepatology. 2016 ; Vol. 64, No. 2. pp. 616-631.
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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. 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).",
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