Research ArticleFIBROSIS

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

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Science Immunology  26 Oct 2018:
Vol. 3, Issue 28, eaar7754
DOI: 10.1126/sciimmunol.aar7754

Type 3 injury

Chronic liver injury caused by infection, toxins, or other inflammatory conditions can lead to liver fibrosis. Several cytokines have been linked to liver fibrosis, and here, Fabre et al. define a role for the type 3 cytokines interleukin-17A (IL-17A) and IL-22 in driving transforming growth factor–β (TGF-β)–dependent fibrosis. They observed elevated levels of IL-17A and IL-22 in intrahepatic lymphocytes from patients with hepatitis. Hepatic stellate cells treated with IL-22 showed enhanced p38 mitogen-activated protein kinase–dependent TGF-β signaling. Liver-resident neutrophils and mast cells were identified as the primary sources of IL-17 in humans, and mouse studies showed that blockade of IL-17A and IL-22 could reduce fibrosis. Together, these findings define a role for type 3 cytokines in driving fibrosis during liver injury.


Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor–β signaling in HSCs in a p38 mitogen-activated protein kinase–dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.

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