Interleukin-17 Signaling in Inflammatory, Kupffer Cells, and Hepatic Stellate Cells Exacerbates Liver Fibrosis in Mice

Abstract

Background IL-17 signaling has been implicated in lung and skin fibrosis. Here we examined the role of IL-17 signaling in the pathogenesis of liver fibrosis. Methods Using cholestatic and hepatotoxic models of liver injury, the development of liver fibrosis in wild type mice was compared to IL-17RA−/− mice, and to bone marrow chimeric mice devoid of IL-17 signaling in immune cells and Kupffer cells (IL-17RA−/−→wt and IL-17A−/− →wt mice), or in liver resident cells (Wt→ IL-17RA−/− mice). Results We determined that IL-17A and its receptor is highly induced in liver injury and has a strong pro-fibrogenic effect on both inflammatory and liver resident cells. IL-17 signaling facilitates production of IL-6, IL-1β, and TNF-α by inflammatory cells, and increases the expression of TGF-β1, the major pro-fibrogenic cytokine. IL-17 directly induces collagen Type I production in hepatic stellate cells (HSCs) via activation of the Stat3 signaling pathway. Mice devoid of Stat3 signaling in HSCs (GFAPStat3−/− mice) are less susceptible to fibrosis. Furthermore, deletion of IL-23 in immune cells results in attenuation of liver fibrosis, while deletion of IL-22 exacerbates fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protects mice from BDL-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms and may serve as an attractive target for anti-fibrotic therapy.

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…found that Stat3 are critical in IL-17A-induced HSC activation and collagen production, and rmIL-17A could promote the expression of a-SMA in isolated HSCs (42). Because Stat3 could be phosphorylated by activated ERK1/2, JNK, or p38 (at Ser 727 ), we further investigated which MAPK pathway may be involved.…”

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

“…IL-17A production triggers several inflammatory conditions (26) and has been implicated in the establishment of liver fibrosis (42) and in the pathogenesis of alcoholic, autoimmune, and hepatitis B virus-or hepatitis C virus-related hepatitis (42)(43)(44)(45). Importantly, in all these chronic inflammatory conditions, IL-17-producing CD4 + T (Th17) cells were reported to be the major source of IL-17A in the liver, with few reports describing IL-17A-producing CD161 + CD8 + T cells (11,45).…”

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…The biological effects of IL-22 are mediated through binding to IL-22 receptors and consequent activation of the STAT3 signaling pathway [224] . IL-22 protects against liver injury [226][227][228][229][230][231] , reduces fat accumulation and collagen deposition [231][232][233][234] and promotes liver regeneration [235,236] in rodent models of ALD. The antifibrotic properties of IL-22 depend on the significant increase of STAT-mediated HSC senescence, as demonstrated by the increase of β-galactosidase-positive HSCs in IL-22-treated animals [237] .…”