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

Sci Immunol. 2018 Oct 26;3(28):eaar7754. doi: 10.1126/sciimmunol.aar7754.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azo Compounds / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Interleukins / antagonists & inhibitors
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pyrazoles / pharmacology
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / metabolism

Substances

  • 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
  • Azo Compounds
  • IL17A protein, human
  • Interleukin-17
  • Interleukins
  • Pyrazoles
  • Transforming Growth Factor beta
  • interleukin-22