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

Background The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4R alpha R576) 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. Objective We examined the interaction between IL-4R alpha R576 and Notch4 in promoting asthmatic inflammation. Methods 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-4R alpha R576 to upregulate Notch4 expression on T-reg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. Results 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-4R alpha R576 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. Conclusion These results identify an IL-4R alpha R576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung T-reg cell function.