A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma
Jörg Köhl, … , John D. Lambris, Marsha Wills-Karp
Jörg Köhl, … , John D. Lambris, Marsha Wills-Karp
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):783-796. https://doi.org/10.1172/JCI26582.
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Research Article Pulmonology

A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma

Abstract

Complement component 5 (C5) has been described as either promoting or protecting against airway hyperresponsiveness (AHR) in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4+CD69+ T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.

Authors

Jörg Köhl, Ralf Baelder, Ian P. Lewkowich, Manoj K. Pandey, Heiko Hawlisch, Lihua Wang, Jennifer Best, Nancy S. Herman, Alyssa A. Sproles, Jörg Zwirner, Jeffrey A. Whitsett, Craig Gerard, Georgia Sfyroera, John D. Lambris, Marsha Wills-Karp

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Figure 1

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Protocols underlying the different models of pulmonary allergy. (A) OVA ...
Protocols underlying the different models of pulmonary allergy. (A) OVA model of inhalation tolerance. Animals were exposed to i.t. OVA at the indicated time points. To block C5aR signaling, animals were treated with anti-C5aR mAb on days –1 and 20. Twenty-four hours after the final allergen exposure, airway responsiveness was determined. Subsequently, BAL, lung tissue, and blood samples were taken. (B) HDM model of pulmonary allergy in which the C5aR was blocked during initial allergen exposure. Animals were exposed to i.t. HDM at the indicated time points (left panel). To block C5aR signaling, animals were treated with the anti-C5aR mAb on days –1, 6, 13, and 20. Seventy-two hours after the final HDM exposure, airway responsiveness was determined. Subsequently BAL, lung tissue, and blood samples were taken. For right panel, procedure was as above, except that the C5aR was blocked by pulmonary expression of the C5aRA. C5aRA expression was initiated 7 days prior to allergen exposure by supplementing the drinking water with dox (0.5 mg/ml). Dox was kept in the drinking water throughout the experiment. (C) Procedure was as in B, except that the C5aR was blocked solely prior to the final HDM exposure on day 20.