A common IL-4 receptor variant promotes asthma severity via a T_reg cell GRB2-IL-6-Notch4 circuit.

Abstract

The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T_reg ) cells in an IL-6-dependent manner. We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation. Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on T_reg cells as a function of IL4R^R576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on T_reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. Asthmatics carrying the IL4R^R576 allele had increased Notch4 expression on their circulating T_reg cells as a function of disease severity and serum IL-6. Mice harboring the Il4ra^R576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon T_reg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung T_reg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung T_reg cell function.