Interleukin-25: a cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome

Churg-Strauss syndrome (CSS) is characterized by systemic vasculitis, and blood and tissue eosinophilia. Blood eosinophilia correlate with disease activity, and activated T cells from CSS patients are predominantly Th2. IL-25 has been shown to link innate and adaptive immunity by enhancing Th2 cytokine production. We sought to determine the involvement of IL-25 and its receptor IL-17RB in the pathogenesis of CSS. We found increased levels of IL-25 in the serum of active patients with CSS (952±697 vs. 75±49 pg/ml in inactive patients and 47±6 pg/ml in healthy donors). IL-25 was correlated with disease activity and eosinophil level. Eosinophils were the main source of IL-25, whereas activated CD4+ memory T cells were the IL-17RB-expressing cells in CSS. IL-25 enhanced the production of IL-4, IL-5 and IL-13 by activated peripheral blood mononuclear cells. IL-25 and IL-17RB were observed within the vasculitic lesions of patients with CSS, and IL-17RB co-localized with T cells. Increased expression of IL-17RB, TRAF6 and JunB in vasculitic lesions of CSS underscored the IL-25-mediated activation, whereas upregulation of GATA3 and IL-10 supported Th2 differentiation. Our findings suggest that eosinophils, through the production of IL-25, exert a critical role in promoting Th2 responses in target tissues of CSS.