TY - JOUR
T1 - Properdin contributes to allergic airway inflammation through local C3a generation
AU - Wang, Yuan
AU - Miwa, Takashi
AU - Ducka-Kokalari, Blerina
AU - Redai, Imre G.
AU - Sato, Sayaka
AU - Gullipalli, Damodar
AU - Zangrilli, James G.
AU - Haczku, Angela Franciska
AU - Song, Wen Chao
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated 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 naive mice. Compared with wild-type (WT) mice, P-deficient (P-/-) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab 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 coadministration 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.
AB - Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated 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 naive mice. Compared with wild-type (WT) mice, P-deficient (P-/-) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab 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 coadministration 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.
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U2 - 10.4049/jimmunol.1401819
DO - 10.4049/jimmunol.1401819
M3 - Article
C2 - 26116506
AN - SCOPUS:84937705037
VL - 195
SP - 1171
EP - 1181
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -