IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist ( Il1rn −/− mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1–, TNF– and IL-17A–dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn −/− mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis in Il1rn −/− mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25 −/− Il1rn −/− mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa —but not Il4 or Il13 —in local lesions compared with Il1rn −/− mice. Tissue–, but not immune cell–, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor–expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn −/− mice, contributing to exacerbation of development of IL-1–, TNF– and IL-17A–dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.