MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming

Morgane Mabire, Pushpa Hegde, Adel Hammoutene, Jinghong Wan, Charles Caër, Rola Al Sayegh, Mathilde Cadoux, Manon Allaire, Emmanuel Weiss, Tristan Thibault-Sogorb, Olivier Lantz, Michèle Goodhardt, Valérie Paradis, Pierre Grange, Hélène Gilgenkrantz and Sophie Lotersztajn ()
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Morgane Mabire: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Pushpa Hegde: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Adel Hammoutene: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Jinghong Wan: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Charles Caër: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Rola Al Sayegh: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Mathilde Cadoux: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Manon Allaire: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Emmanuel Weiss: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Tristan Thibault-Sogorb: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Olivier Lantz: Institut Curie, INSERM U932
Michèle Goodhardt: Université Paris Cité, INSERM UMRS 976, Institut de Recherche Saint Louis
Valérie Paradis: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Pierre Grange: GenoSplice
Hélène Gilgenkrantz: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex
Sophie Lotersztajn: Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37453-5

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