Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation

Abstract

Complement is implicated in asthma pathogenesis but its mechanism of action in this disease remains incompletely understood. Here we studied the role of properdin (P), a positive alternative pathway complement regulator, in allergen-induced airway inflammation. Allergen challenge stimulated P release into the airways of asthmatic patients and P levels positively correlated with proinflammatory cytokines in human bronchoalveolar lavage (BAL). High levels of P were also detected in the BAL of OVA-sensitized and challenged but not naïve mice. Compared with wild-type mice, P-deficient (P−/−) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Antibody blocking of P at both sensitization and challenge phases or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of P to P−/− mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA-challenged P−/− mice were significantly lower than in wild-type mice, and intranasal co-administration of an anti-C3a mAb with P to P−/− mice prevented restoration of airway inflammation. These results show that P plays a key role in allergen-induced airway inflammation and represents a potential therapeutic target for human asthma.

Anti-complement activity of the Ixodes scapularis salivary protein Salp20

“…2D). These results are consistent with a recent report demonstrating that properdin plays a critical role in OVA-induced asthma phenotype [39]. To examine Salp20 activity in this asthma model, WT mice were sensitized with OVA as above.…”

Old dogs—new tricks: immunoregulatory properties of C3 and C5 cleavage fragments

“…Several reports found important contributions of factors B and H for the development of airway hyperresponsiveness (AHR) and airway inflammation during the effector phase suggesting massive local alternative pathway activation in established asthma. In line with these findings, local properdin production, and subsequent generation of C3a contributes to allergic airway inflammation . C3a induces the expression of Muc5AC and promotes the recruitment of inflammatory cells by bronchial ECs .…”

Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma

“…Yet even in established plasma exudative conditions, such as after airway allergen challenge in atopic subjects, 100,102 local production of complement proteins has been forwarded as the preferred source. 103,104 As demonstrated in sensitized guinea pigs and in patients with allergic rhinitis and allergic asthma, allergen challenge has caused both early-and late-phase plasma exudation responses. 27,105,106 Yet in studies in which appearance of complement and coagulation products would reflect this biphasic feature, the role of plasma exudation has not been considered.…”