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

Abstract

UNLABELLED:

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).

• Authors: 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
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 64 Issue 2 Pg. 616-31 (08 2016) ISSN: 1527-3350 [Electronic] United States
• PMID: 27178735 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by the American Association for the Study of Liver Diseases.

Chemical References

• Interleukin-17
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Receptors, Antigen, T-Cell, gamma-delta
• TLR3 protein, mouse
• Toll-Like Receptor 3

Topics

• Animals
• Carbon Tetrachloride Poisoning (metabolism)
• Exosomes
• Hepatic Stellate Cells (metabolism)
• Interleukin-17 (metabolism)
• Liver Cirrhosis (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Nuclear Receptor Subfamily 1, Group F, Member 3 (metabolism)
• Receptors, Antigen, T-Cell, gamma-delta (metabolism)
• T-Lymphocytes (metabolism)
• Toll-Like Receptor 3 (metabolism)