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    Obesity: Mucosal-associated immune cells induce intestinal inflammation and dysbiosis

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    Team Agnès Lehuen

    Obesity: Mucosal-associated immune cells induce intestinal inflammation and dysbiosis

     

    In an article published in the journal Nature Communications, the team directed by Agnès Lehuen demonstrates the important role of MAIT cells (Mucosal Associated Invariant T cells) in chronic inflammation of adipose tissue and intestinal dysbiosis in a context of obesity. The results shed light on the immune mechanisms involved in the development of type 2 diabetes in obesity and point to MAIT cells as potential new therapeutic targets in obesity and type 2 diabetes.

    Obesity is a pathology with an inflammatory component, the prevalence of which is increasing worldwide. Immune cells play an important role in the development of this disease and especially in adipose tissue with the development of chronic inflammation. MAIT cells are unconventional T lymphocytes, restricted by the non-polymorphic molecule MR1, presenting bacterial metabolites derived from vitamin B2 or riboflavin. These cells have the ability to produce cytokines including IL-2, IFN-γ, TNFα, IL-17 and granzyme B. In a previous study, the team described deregulation of MAIT cells in the blood and adipose tissue of obese and / or diabetic subjects, showing that MAIT cells represented a biomarker of the development of diabetes but without determining whether the alterations in MAIT cells were the consequence or the cause of the metabolic dysfunctions associated with obesity and type 2 diabetes. This new study using mouse models highlights the deleterious role of MAIT cells in obesity and the development of type 2 diabetes.

     

    The authors observed in several mouse models of obesity (genetic and nutritional) alterations in the phenotype and function of MAIT cells in adipose tissue similar to those seen in patients. These changes have also been observed in the intestine (ileum) but not in other organs. The role of MAIT cells in obesity was therefore analyzed, by studying transgenic mice with an increased number of MAIT cells or in contrast mice lacking MAIT cells, all mice being fed with a high fat diet. Mice expressing large numbers of MAIT cells develop inflammation in adipose tissue and ileum, insulin resistance, and impaired glucose and lipid metabolism. Conversely, the absence of MAIT cells decreases inflammation in these tissues and improves metabolic parameters. In the intestine, MAIT cells participate in dysbiosis (imbalance of the intestinal microbiota) and in the loss of the integrity of the intestinal barrier. These tissue alterations contribute to metabolic dysfunction.

    The inflammatory mechanism of MAIT cells induces changes in other immune cells in adipose tissue and in the ileum. In obesity, MAIT cells promote the polarization of M1-type (pro-inflammatory) macrophages and this polarization results from a direct interaction between MAIT cells and macrophages. In obese mice, injection of ligand blocking this interaction between MAIT cells and macrophages decreases inflammation of adipose tissue, intestinal dysbiosis and metabolic dysfunctions.

     

    These results suggest that MAIT cells could represent a new therapeutic target for the treatment of obesity and type 2 diabetes.

     

    Reference

    Mucosal-Associated Invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Toubal A*, Kiaf B*, Beaudoin L, Cagninacci L, Rhimi M, Fruchet B, da Silva J, Corbett A, Simoni Y, Lantz O, Rossjohn J, McCluskey J, Lesnik P, Maguin E, Lehuen A.  Nat Commun. July 2020.     doi : 10.1038/s41467-020-17307-0

     

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