Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

Abstract

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Complement Activation Pathways: A Bridge between Innate and Adaptive Immune Responses in Asthma

“…Through binding their receptors on inflammatory cells and resident airway cells, C5a and C3a have been shown to induce many of the pathophysiologic features of allergic asthma, such as smooth muscle contraction, increased vascular permeability, mucus secretion, and recruitment of inflammatory cells. In support of its pro-allergic role, studies in which C5a has been inhibited pharmacologically after initial allergen sensitization have shown that C5a plays an important role in driving allergen-driven AHR and airway inflammation in mouse models of asthma (17)(18)(19). However, C5a does not directly induce smooth muscle contraction in the mouse airway, suggesting that C5aR ligation of resident airway cells is not sufficient to induce ASM contraction (20).…”

Functional roles for C5a receptors in sepsis

“…In additional experiments, we injected wildtype mice with 200 μl of a C5a receptor antagonist that blocks C5ar and C5l2 (10 μM; (A8 Δ71-73 ) 17 at 0 h, 12 h and 24 h after CLP. Alternatively, we injected Gpr77 -/-mice with 100 μg of a monoclonal rat antibody to mouse C5ar (clone 20/70; AbD Serotec) 36,37 or monoclonal control rat IgG2b (AbD Serotec). For neutralization of C5a, we injected wild-type mice intravenously with polyclonal rabbit antibody to mouse C5a (40 μg; R&D Systems) or nonspecific rabbit IgG (Jackson Immunoresearch).…”

C5a receptor signalling in dendritic cells controls the development of maladaptive Th2 and Th17 immunity in experimental allergic asthma

“…By contrast, blocking the C5aR during the allergic effector phase attenuates the allergic phenotype. 6,12,13 The increased maladaptive Th2 response following C5aR targeting is associated with an increased ratio of cDCs vs. pDCs and a decreased expression of B7-H1 and B7-DC on pDCs, 14 suggesting that C5a may directly regulate DC activity in the lung through C5aR activation. In support of this view, C5aR…”