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

Greater production of interleukin 17A is associated with severe asthma. Wills-Karp and colleagues show that the complement anaphylatoxins C3a and C5a have opposing roles in enhancing or suppressing IL-17a in allergic asthma. Severe asthma is associated with the production of interleukin 17A (IL-17A). The exact role of IL-17A in severe asthma and the factors that drive its production are unknown. Here we demonstrate that IL-17A mediated severe airway hyperresponsiveness (AHR) in susceptible strains of mice by enhancing IL-13-driven responses. Mechanistically, we demonstrate that IL-17A and AHR were regulated by allergen-driven production of anaphylatoxins, as mouse strains deficient in complement factor 5 (C5) or the complement receptor C5aR mounted robust IL-17A responses, whereas mice deficient in C3aR had fewer IL-17-producing helper T cells (T H 17 cells) and less AHR after 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.