MAIT cells protect against alcohol-associated liver injury via an IL-10–macrophage–CXCL1 axis

Abstract Mucosal-associated invariant T (MAIT) cells are enriched in the liver and contribute to immune regulation, but their role in alcohol-associated liver disease (ALD), particularly in neutrophil-driven inflammation, remains unclear. We examined MAIT cell frequency and function in blood from ALD patients and in the liver, spleen, and peripheral blood from ethanol-fed mice, and used wild-type and MR1-deficient (MR1 −/− ) mice exposed to chronic-binge and acute ethanol, with 5-OP-RU, recombinant IL-10, or a CXCL1-neutralizing antibody as interventions. MAIT cells were reduced in ALD patients and ethanol-fed mice, and showed an activated but functionally impaired phenotype. MAIT cell deficiency aggravated ethanol-induced liver injury, steatosis, oxidative stress, and inflammation, whereas 5-OP-RU–mediated expansion was protective. RNA-seq and flow cytometric analyses revealed that MAIT cell deficiency was associated with increased accumulation of monocyte-derived macrophages (MoMFs) and enhanced CD86 expression, whereas Kupffer cells (KCs) showed no significant phenotypic changes. MAIT cells preferentially regulated MoMFs rather than hepatocytes, thereby restraining CXCL1 production and hepatic neutrophil recruitment. Mechanistically, this regulation depended on MAIT-derived IL-10, as either IL-10 administration or CXCL1 blockade attenuated liver injury in ethanol-fed MR1 −/− mice. Overall, our data define a MAIT–IL-10–macrophage–CXCL1 axis that restrains neutrophil-driven inflammation in ALD and represents a regulatory checkpoint in disease progression.