Levels of the
anaphylatoxin C3a are increased in patients with
asthma compared with those in nonasthmatics and increase further still during
asthma exacerbations. However, the role of C3a during sensitization to
allergen is poorly understood. Sensitization to fungal
allergens, such as Aspergillus fumigatus, is a strong risk factor for the development of
asthma. Exposure to
chitin, a structural
polysaccharide of the fungal cell wall, induces innate allergic
inflammation and may promote sensitization to fungal
allergens. Here, we found that coincubation of
chitin with serum or intratracheal administration of
chitin in mice resulted in the generation of C3a. We established a model of
chitin-dependent sensitization to soluble Aspergillus
antigens to test the contribution of
complement to these events. C3(-/-) and C3aR(-/-) mice were protected from
chitin-dependent sensitization to Aspergillus and had reduced lung
eosinophilia and type 2
cytokines and serum
IgE. In contrast,
complement-deficient mice were not protected against
chitin-induced innate allergic
inflammation. In sensitized mice, plasmacytoid dendritic cells from
complement-deficient animals acquired a tolerogenic profile associated with enhanced regulatory T cell responses and suppressed Th2 and Th17 responses specific for Aspergillus. Thus,
chitin induces the generation of C3a in the lung, and
chitin-dependent allergic sensitization to Aspergillus requires C3aR signaling, which suppresses regulatory dendritic cells and T cells and induces
allergy-promoting T cells.