The team of S Loterstajn and H Gilgenkrantz, in collaboration with V Paradis whithin the Centre de Recherche sur l’Inflammation, and the teams of O Lantz (I Curie) and M Goodhardt (Institut St Louis) recently showed that MAIT cell inhibition not only stops liver fibrosis progression but also promotes fibrosis regression. In analyzing the mechanisms involved, the authors showed that blocking MAIT cell activation inhibits the dialog with profibrogenic macrophages and promotes the emergence of resolutive macrophages. These results open new therapeutic perspectives for liver cirrhosis.


Recent data have shown that liver fibrosis can regress even at later stages of cirrhosis and shifting the immune response from pro-inflammatory towards a resolutive profile is considered as a promising option. The immune regulatory networks that govern the shift of the inflammatory phenotype and thus potential reversal of liver fibrosis are lesser known. Here we show that in precision-cut human liver slices obtained from patients with end-stage fibrosis and in mouse models, inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches, limits fibrosis progression and even regresses fibrosis, following chronic toxic- or non-alcoholic steatohepatitis (NASH)-induced liver injury. Mechanistic studies, combining RNA sequencing, in vivo functional studies (performed in male mice) and co-culture experiments indicate that disruption of the MAIT cell-monocyte/macrophage interaction results in resolution of fibrosis both by increasing the frequency of restorative Ly6Clo at the expenses of pro-fibrogenic Ly6Chi monocyte-derived macrophages and promoting an autophagic phenotype in both subsets. Thus, our data show that MAIT cell activation and the consequential phenotype shift of liver macrophages are important pathogenic features of liver fibrosis and could be targeted by anti-fibrogenic therapy.

This study is published in Nature Communications : 2023 Apr 1;14(1):1830. doi: 10.1038/s41467-023-37453-5. PMID: 37005415