Absence of the Complement Anaphylatoxin C3a Receptor Suppresses Th2 Effector Functions in a Murine Model of Pulmonary Allergy

Abstract

Asthma is a chronic inflammatory disease of the lung resulting in airway obstruction. The airway inflammation of asthma is strongly linked to Th2 lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which regulate airway hyperresponsiveness, eosinophil activation, mucus production, and IgE secretion. Historically, complement was not thought to contribute to the pathogenesis of asthma. However, our previous reports have demonstrated that complement contributes to bronchial hyperreactivity, recruitment of airway eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary allergy. To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA. Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR-deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4-producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases in IgE titers as well as reduced mucus production. Collectively, these data highlight the importance of complement activation, the C3a anaphylatoxin, and its receptor during Th2 development in this experimental model and implicate these molecules as possible therapeutic targets in diseases such as asthma.

Complement C3a-Induced IL-17 Plays a Critical Role in an IgE-Mediated Late-Phase Asthmatic Response and Airway Hyperresponsiveness via Neutrophilic Inflammation in Mice

“…These results show that suppression of the late-phase increase in airway resistance and AHR by the antagonist or the mAb was not related to the production of Th2-type cytokines. However, there have been conflicting reports: C3a receptor-deficient mice sensitized with mixed OVA and Aspergillus fumigatus (44) or house dust mites (45) showed reduced cytokine levels and AHR. Kumar and Foster (46) have suggested that the roles of cells and molecules in AHR were altered by changing the protocol (dose and duration) for the challenge, indicating that the role of C3a in the pathogenesis of asthma also varies depending on the protocol used.…”

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

“…Similar effects have been shown for C3a. Specifically, several groups have now shown that deficiencies in C3 (21,22) or the C3aR (7,23,24) protect against the development of allergen-driven AHR. Likewise, the AHR induced by exposure to several environmental stimuli, including RSV (11), particulate matter (22), and ozone (9), has been shown to be C3-dependent.…”

Human Skin Mast Cells Express Complement Factors C3 and C5

“…Local production of C3 by dendritic cells in mice, for example, promotes Th1 development (41,47). C3a can amplify pathologic process by increasing vasopermeability, contracting bronchial smooth muscle, stimulating dendritic cells to modulate T cell activation, or activating mast cells and basophils, of likely importance in allergic disorders such as asthma and in autoimmune urticaria (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98). Furthermore, C3adesArg, a metabolite of C3a, serves as an adipokine associated with obesity, type II diabetes, and coronary artery disease (99).…”