Anaphylatoxin C3a receptors in asthma

Abstract

The complement system forms the central core of innate immunity but also mediates a variety of inflammatory responses. Anaphylatoxin C3a, which is generated as a byproduct of complement activation, has long been known to activate mast cells, basophils and eosinophils and to cause smooth muscle contraction. However, the role of C3a in the pathogenesis of allergic asthma remains unclear. In this review, we examine the role of C3a in promoting asthma. Following allergen challenge, C3a is generated in the lung of subjects with asthma but not healthy subjects. Furthermore, deficiency in C3a generation or in G protein coupled receptor for C3a abrogates allergen-induced responses in murine models of pulmonary inflammation and airway hyperresponsiveness. In addition, inhibition of complement activation or administration of small molecule inhibitors of C3a receptor after sensitization but before allergen challenge inhibits airway responses. At a cellular level, C3a stimulates robust mast cell degranulation that is greatly enhanced following cell-cell contact with airway smooth muscle (ASM) cells. Therefore, C3a likely plays an important role in asthma primarily by regulating mast cell-ASM cell interaction.

Figure 1

Model for C3a generation in individuals with asthma. C3 may be secreted from pulmonary resident cells (e.g. epithelial cells and macrophages) or derived from plasma leakage. Antibody (IgG) present in the serum of sensitized individual can form a complex with allergen to activate complement via the classical pathway. Proteases derived from allergen or released from activated mast cells are able to cleave C3 to generate C3a. Activation of alternative or the lectin pathway on the allergen together with factors B, H, and I and properdin released resident cells may generate C3a.

Figure 2

Proposed interaction between FcεRI and C3aR leading to mast cell activation. Allergen cross-links FcεRI on mast cells to induce degranulation. Allergen can also activate complement pathway (see Fig. 1) to generate C3a, which in turn activates its cognate G protein coupled receptors on mast cells to induce degranulation. Mast cell proteases also activates complement cascade to generate C3a. This C3a may serve to amplify mast cell mediator release.

Figure 3

Model for the role C3a in AHR and airway inflammation in asthma. C3a generated in individuals with asthma (see Fig. 1) induces mast degranulation (Fig. 2) to promote ASM force generation. Chemokines and cytokines expressed by ASM recruit and retain mast cells into the ASM layer resulting in further smooth muscle dysfunction. T_H2 cytokines and chemokines generated from mast cells (and possibly eosinophils and bronchial epithelial cells) regulate AHR and airway inflammation.