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Properdin Contributes to Allergic Airway Inflammation Through Local C3a Generation Yuan Wang, Takashi Miwa, Blerina Ducka-Kokalari, Imre G

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Properdin Contributes to Allergic Airway Inflammation Through Local C3a Generation Yuan Wang, Takashi Miwa, Blerina Ducka-Kokalari, Imre G Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation Yuan Wang, Takashi Miwa, Blerina Ducka-Kokalari, Imre G. Redai, Sayaka Sato, Damodar Gullipalli, James G. This information is current as Zangrilli, Angela Haczku and Wen-Chao Song of September 26, 2021. J Immunol 2015; 195:1171-1181; Prepublished online 26 June 2015; doi: 10.4049/jimmunol.1401819 http://www.jimmunol.org/content/195/3/1171 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/06/26/jimmunol.140181 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 66 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/195/3/1171.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation Yuan Wang,* Takashi Miwa,* Blerina Ducka-Kokalari,† Imre G. Redai,† Sayaka Sato,* Damodar Gullipalli,* James G. Zangrilli,‡ Angela Haczku,† and Wen-Chao Song* 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 cor- related 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 (P2/2) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab Downloaded from 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 P2/2 mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA-challenged P2/2 mice were significantly lower than in wild-type mice, and intranasal coadministration of an anti-C3a mAb with P to P2/2 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. The Journal of Immunology, 2015, 195: 1171–1181. http://www.jimmunol.org/ llergic asthma is a chronic inflammatory disease char- Properdin (P) is a plasma glycoprotein and the only known acterized by pulmonary eosinophilia, increased serum positive regulator of the complement cascade (21). It binds to and A IgE levels, airway hyperresponsiveness (AHR), mucous stabilizes the alternative pathway (AP) C3 convertase C3bBb (21, hypersecretion, and structural remodeling of airways (1). Current 22) and, in some cases, may also serve as a platform to form new treatment for asthma such as systemic corticosteroids and inhaled C3bBb convertases on the cell surface (23). P is best known as b agonists are far from optimal, and there is a need to develop a promoter of AP complement activation in the context of host novel therapeutic approaches, particularly for those patients with defense, and its deficiency in humans increases the risk for by guest on September 26, 2021 severe asthma (2). Asthma is believed to be driven by inappro- Neisseria meningitidis infection (24–27). There is considerable priate Th2-dominated immune responses to environmental aller- evidence to suggest that P may also play a critical role in AP gens (3–6). In addition, the role of innate immunity in asthma has complement-mediated tissue injury, for example, in the setting of also attracted interest of investigators (7–10). Complement is ischemia reperfusion injury or inflammatory joint destruction a key component of the host innate immunity, and previous (28, 29). In contrast, P deficiency or inhibition in a murine model clinical and laboratory studies have suggested an important role of fH-related C3 glomerulopathy exacerbated glomerular disease of the complement system in this disease (11–20). A better (30), suggesting that the role of P in AP complement-mediated understanding of the activation mechanisms and effectors of diseases may be complex and potentially context specific. Previ- complement in asthma would aid the development of novel anti- ous studies have found the AP complement and anaphylatoxin complement therapies. receptors to be involved in murine models of asthma, but whether and how P might play a role in this disease is not known. In this study, we tested the hypothesis that P contributes to the patho- *Department of Systems Pharmacology and Translational Therapeutics, Perelman genesis of allergen-induced airway inflammation and that target- School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; †Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Penn- ing P dampens Th2 and Th17 immune responses. Our study sylvania, Philadelphia, PA 19104; and ‡Thomas Jefferson University Hospital, Phil- provides proof of concept for therapeutic targeting of P in allergic adelphia, PA 19107 asthma. Received for publication July 17, 2014. Accepted for publication May 23, 2015. This work was supported by National Institutes of Health Grants R21AI103965, Materials and Methods RO1AI044970, and RO1AI085596 (to W.-C.S.) and Grants RO1AI072197, RC1ES018505, and P30ES013508 (to A.H.). Human patient samples Address correspondence and reprint requests to Dr. Wen-Chao Song, Department of All subjects gave their informed consent, and the study was approved by Systems Pharmacology and Translational Therapeutics, Perelman School of Medi- the Institutional Review Board of the Thomas Jefferson Medical College. cine, University of Pennsylvania, Room 1254 BRBII/III, 421 Curie Boulevard, Phil- Deidentified bronchoalveolar lavage (BAL) samples were obtained from adelphia, PA 19104. E-mail address: [email protected] study subjects as described before (31). In brief, healthy subjects without The online version of this article contains supplemental material. asthma and subjects with allergic asthma and rhinitis were recruited for the Abbreviations used in this article: AHR, airway hyperresponsiveness; AP, alternative study and screened to assess suitability. Screening consisted of medical pathway; BAL, bronchoalveolar lavage; MLN, mediastinal lymph node; P, properdin; history and physical examination, followed by skin testing for allergy to PAS, periodic acid–Schiff reagent; RL, lung resistance; WT, wild-type. common aeroallergens. All subjects were nonsmokers and were not taking any chronic medications. Asthmatics met the National Institutes of Health/ Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 National Heart, Lung, and Blood Institute expert panel criteria for the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401819 1172 PROPERDIN AND ALLERGIC ASTHMA diagnosis of asthma, and the diagnosis was confirmed by spirometry and immediately before each OVA challenge (Fig. 7A). P2/2 mice receiving responsiveness to methacholine (32). In an effort to reduce variability, only recombinant P premixed with the anti-P mAb were used as controls. To a single allergen was used, ragweed Ag E (Amb a I), and patients were evaluate the role of C3a, we included a rat anti-mouse C3a mAb (5 mg/ studied outside of ragweed season. The concentration of the lung-delivered mouse) with recombinant P in some of the reconstitution experiments dose of ragweed Ag was determined by serial intradermal skin testing and (Fig. 8C). was 100-fold higher than that required to cause a minimum positive skin wheal, based on our established protocol (31). In brief, on day 1, the Collection of BAL and cell counts subject presented between the hours of 7:00 and 9:00 AM and underwent BAL with 150 ml saline in 50-ml aliquots in a lingular segment. This was After serum collection, mice were sacrificed and lungs were lavaged as immediately followed by Ag instillation into a right middle lobe segmental previously described (34). In brief, the left lung was ligated, trachea was bronchus. For safety reasons, a 10-fold test dose preceded instillation of cannulated, and the right lung was lavaged with 500 ml PBS three times. the full challenge dose. Both test and challenge volumes were 5 ml. On day Cell counting was performed on cytospin preparations stained with May– € 2, the challenged segment was lavaged in the same way as on day 1. For Grunwald–Giemsa (Merck), and at least 200 cells were classified in this study, paired
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