Journal Article

MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming

Hegde, Pushpa, Cadoux, Mathilde, Goodhardt, Michèle, Hammoutene, Adel, Caër, Charles, Thibault-Sogorb, Tristan, Gilgenkrantz, Hélène, Lantz, Olivier, Wan, Jinghong, Weiss, Emmanuel, Sayegh, Rola Al, Allaire, Manon, Paradis, Valérie, Lotersztajn, Sophie, de la Grange, Pierre, Mabire, Morgane

2023

Overview

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 Ly6C lo at the expenses of pro-fibrogenic Ly6C hi 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. Liver cirrhosis is characterised by extensive fibrosis of the liver, and understanding the underpinning immunological processes is important in designing intervention. Here authors show that Mucosal-Associated Invariant T cells are instrumental to controlling the balance between profibrogenic and restorative macrophages and inhibiting their activation might reverse liver fibrosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/31 / 13/51 / 14/1 / 14/19 / 38 / 38/77 / 38/91 / 59 / 631/1647/514/1949 / 631/250/2504/2506 / 631/250/2504/342 / 692/699/1503/1607/1605 / Animal models / Animals / Antibodies / Biocompatibility / Cell activation / Cell culture / Cirrhosis / Fibrosis / Gene sequencing / Genotype & phenotype / Hepatocytes / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunology / In vivo methods and tests / Inflammation / Invariants / Liver / Liver - pathology / Liver cirrhosis / Liver Cirrhosis - pathology / Lymphocytes / Lymphocytes T / Macrophages / Male / Mice / Mice, Inbred C57BL / Monocytes / Mucosa / Mucosal-Associated Invariant T Cells / multidisciplinary / Non-alcoholic Fatty Liver Disease - pathology / Phenotype / Phenotypes / Science / Science (multidisciplinary)