Rôles distinctifs des inflammations de type II et III dans la progression de la fibrose hépatique
Inflammatory immune cells can modulate activation of hepatic stellate cells (HSC) and progression of liver fibrosis. Inflammation is divided in three types characterized by distinct cytokine profiles. Type I inflammation (characterized by IFN-γ production) has anti-fibrogenic properties in contrast to type II inflammation (characterized by IL-4 and IL-13 production). Type III inflammation characterized by production of IL-17 and IL-22 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.  In these studies, we evaluated the contribution of type III inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs and in vivo mouse models. We report dysregulated type II responses during non-alcoholic steatohepatitis (NASH). This signature was validated in vivo, where we demonstrated that type II inflammation limited metabolic syndrome associated with NASH, but contributed to liver fibrosis progression. We also report dysregulated type III responses in fibrotic lesions with increased Th17/Treg ratio as well as elevated IL-17A and IL-22 production in liver biopsies. We demonstrate that IL-17A sensitizes HSCs to the action of TGF-β through up-regulation of the TGF-β-RII in a JNK-dependent manner. In addition, we also demonstrate a new pro-fibrotic function of IL-22 through enhancement of TGF-β signaling in HSCs in a p38 MAPK dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking IL-22 production using aryl hydrocarbon receptor (AHR) or RORγt antagonist led to reduced fibrosis.  Altogether, we identified a novel role for type III inflammation mediated by IL-17A and IL-22 in driving liver fibrosis during chronic liver injury.
Inflammation Th17 Fibrosis Immunity Chronic liver injury