Type 3 innate lymphoid cell: a new player in liver fibrosis progression.

Type 3 innate lymphoid cell (ILC3) has recently emerged as a crucial effector in inflammatory and fibrotic diseases. The present study was designed to determine the roles of ILC3 in liver fibrosis. By flow cytometry, we documented increased frequencies of peripheral ILC3 (Lin-CD127+CD117+CD294- lymphocytes) in patients, especially at the advanced stage of hepatitis B virus (HBV)-related chronic liver diseases, and demonstrated their correlations with disease progression. The in vitro fibrogenic effects by ILC3 were determined by co-culture experiments with LX-2 (a human hepatic stellate cell (HSC) line). The data indicate that pathogenic ILC3 can directly promote LX-2 fibrogenesis in non-contact manners by producing interleukin (IL)-17A and IL-22. Additionally, they had indirect fibrogenic effects by producing IL-22 to suppress interferon (IFN)-γ (a well-known anti-fibrotic cytokine) production by other immune cells. In carbon tetrachloride (CCl4)-induced wild-type mouse liver fibrosis models, we also documented significantly increased frequencies of both non-natural killer (NK) ILC (Lin-CD127+ lymphocytes) and ILC3 (Lin-CD127+RORγt+ lymphocytes) in liver and spleen specimens. Furthermore, the ILC3 from fibrotic mice contained more IL-17A+ILC3 and IL-22+ILC3 subsets than those from normal and less-fibrotic mice. The in vivo effects of ILC3 in liver fibrogenesis were further determined using RAG-1-/- mice with ILC depletion and further adoptive transfer of ILC3 from wild-type mice. The immunohistochemical staining of liver specimens showed the beneficial effects by ILC depletion and the detrimental effects by ILC3 transfer in CCl4-induced mouse liver fibrosis models. Collectively, ILC3 plays a pro-fibrotic role in liver fibrosis progression.

Wang S ，Li J ，Wu S ，Cheng L ，Shen Y ，Ma W ，She W ，Yang C ，Wang J ，Jiang W ... -  《-》

Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.

Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA(-/-) mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA(-/-) to wild-type and IL-17A(-/-) to wild-type mice) or liver resident cells (wild-type to IL-17RA(-/-) mice). In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3(-/-) mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.

Meng F ，Wang K ，Aoyama T ，Grivennikov SI ，Paik Y ，Scholten D ，Cong M ，Iwaisako K ，Liu X ，Zhang M ，Österreicher CH ，Stickel F ，Ley K ，Brenner DA ，Kisseleva T ... -  《-》

IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation.

Tan Z ，Qian X ，Jiang R ，Liu Q ，Wang Y ，Chen C ，Wang X ，Ryffel B ，Sun B ... -  《-》

Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines.

Lu DH ，Guo XY ，Qin SY ，Luo W ，Huang XL ，Chen M ，Wang JX ，Ma SJ ，Yang XW ，Jiang HX ... -  《-》

Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes.

Zhang XW ，Mi S ，Li Z ，Zhou JC ，Xie J ，Hua F ，Li K ，Cui B ，Lv XX ，Yu JJ ，Hu ZW ... -  《Oncotarget》