Complement-mediated regulation of the interleukin 17A axis is a central genetic determinant of the severity of experimental allergic asthma

Severe asthma is associated with interleukin 17A (IL-17A) production. The exact role of IL-17A in severe asthma and the factors driving its production are unknown. Here we have demonstrated that IL-17A mediated severe airway hyperresponsiveness (AHR) in susceptible strains of mice by enhancing IL-13-driven responses. Mechanistically, we have demonstrated that IL-17A and AHR were regulated by allergen-driven production of anaphylatoxins, as complement factor 5 (C5) and C5aR-deficient strains mounted robust IL-17A responses, while C3aR-deficient mice had reduced T(H)17 cells and AHR following allergen challenge. The opposing effects of C3a and C5a were mediated through their reciprocal regulation of IL-23 production. These data demonstrate a critical role for complement-mediated regulation of the IL-23–T(H)17 axis in severe asthma.