Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a

Abstract

Allergic diseases such as asthma result from inappropriate immunologic responses to common environmental allergens in genetically susceptible individuals. Following allergen exposure, interaction of dendritic cells (DC) with CD4(+) T cells leads to the production of Th2 cytokines, which induce B cells to synthesize IgE molecules (sensitization phase). These IgE molecules bind to their high affinity receptors (FcvarepsilonRI) on the surface of mast cells and basophils and their subsequent cross-linking by allergen results in the release of preformed and newly synthesized mediators, which cause bronchoconstriction, lung inflammation and airway hyperresponsiveness (AHR) in asthma (effector phase). The complement components C3a and C5a levels are increased in the lungs of patients with asthma and are likely generated via the actions of both allergen and mast cell proteases. In vivo studies with rodents have shown that while C3a facilitates allergen sensitization in some models C5a inhibits this response. Despite this difference, both anaphylatoxins promote lung inflammation and AHR in vivo indicating that cells other than DC and T cells likely mediate the functional effects of C3a and C5a in asthma. This review focuses on the contribution of C3a and C5a in the pathogenesis of asthma with a particular emphasis on mast cells and basophils. It discusses the mechanisms by which anaphylatoxins activate mast cells and basophils and the associated signaling pathways via which their receptors are regulated by priming and desensitization.

Fig. 1. Model for the role of FcεRI and mast cells on C3a and C5a generation and amplification of mediator release

Mast cell numbers are increased in the lung of allergic individuals, which are likely to be activated via FcεRI. The release of mast-derived mediators such as histamine causes increase in vascular permeability and the resulting exudation likely contains C3 and C5. Tryptase released from activated mast cells act on C3 and C5 to locally generate C3a and C5a. These anaphylatoxins activate MC_TC mast cells present in bronchial smooth muscle to further exacerbate symptoms associated with asthma. See text and Fukuoka et al., [81] for further detail. GPCR-independent pathway for the action of C3a is not shown (See Section 3.4).

Fig. 2. Possible role of basophil-derived IL-3 on the priming of C3a and C5a-induced mediator release

IL-3 generated via the activation of FcεRI in basophils interacts with it s cell surface receptors on basophils to prime both C3a-induced histamine release and LTC₄ generation. IL-3 also enhances C5a-induced histamine release, LTC₄ generation (early phase and later phase) as well as Th2 cytokines IL-4 and IL-13. These basophil-derived mediators are likely to have profound influence on allergen sensitization, bronchial smooth contraction and delayed inflammation.

Fig. 3. Model for the role of GRKs and β-arrestin on the regulation of C3a and C5a receptors

C3a and C5a bind to their GPCRs on mast cells and basophils to activate PLCβ, cPLA₂ and NF-κB to induce release of different mediators. IL-3 enhances C3a and C5a-induced mediator release in human basophils. Effects of IL-3 on enhanced C5a-induced LTC₄ generation involves ERK phosphorylation (early) and greater C5a-induced Ca²⁺ mobilization (late) (Blue dotted lines). Receptor phosphorylation by GRKs serves to recruit β-arrestin and this complex interacts with G protein to desensitize degranulation and LTC₄ generation. Internalized β-arrestin-associated receptor inhibits NF-κB activation to block delayed cytokine gene expression (red lines).