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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Generation and characterization of C5aRA Tg mice. (A) Generation of C5aR...
Generation and characterization of C5aRA Tg mice. (A) Generation of C5aR Tg mice (see Methods). rCCSP, rat clara cell–specific promoter; hGHpA, human growth hormone polyadenylation signal; bGHpA, bovine growth hormone polyadenylation signal. (B, upper left panel) Ccsp-rtTa sTg mice (545 bp, lane 1) were bred to (tetO)7-CMV-C5aRA sTg mice (228 bp, lane 2) to generate C5aRA-Cssp dTg progeny (C5aRA-Ccsp dTg, lane 3). M, marker (200–900 bp). (Upper right panel) Kinetic of induction of pulmonary C5aRA mRNA in C5aRA-Ccsp dTg mice. RT-PCR was performed from whole-lung samples of C5aRA-Ccsp dTg mice that received drinking water without dox (day 0) or dox-supplemented water (0.5 mg/ml) for 1 day, 3 days, or 7 days. Control reactions with GAPDH primers are shown in the lower panel. (Lower panel) Organ specificity of Tg activation in C5aRA-Ccsp dTg mice treated with dox for 7 days. Lane 1, lung from C5aRA sTg mouse; lanes 2–7, liver, spleen, kidney, heart, brain, and lung from C5aRA-Ccsp dTg mouse; lane 8, genomic DNA from C5aRA-Ccsp dTg (positive control). (C) C5aRA protein expression in lung epithelial cells (indicated by arrows) from C5aRA-Ccsp dTg mice treated for 7 days with dox. Immunohistochemical staining using anti-C5a mAb 561: Alexa488 (left panel); ISO-Ctrl (right panel). We found no C5aRA protein expression in lung epithelial cells of C5aRA sTg mice treated with dox (data not shown). (D, left panel) Total and differential cell counts in BAL. (Right panel) Cytokine profile of pulmonary cells harvested from BALB/c mice 72 hours after final in vivo HDM exposure. Cytokine profiles and BAL cell counts obtained from HDM-exposed non-Tg littermates were indistinguishable from those of HDM-exposed C5aRA sTg mice (data not shown). *P < 0.05; **P < 0.001.