A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma

Division of Molecular Immunology,Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(11):6741-52. DOI: 10.4049/jimmunol.1000892
Source: PubMed


The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The functional role of C5L2 in vivo remains enigmatic. In this study, we show in two models of OVA- and house dust mite (HDM)-induced experimental allergic asthma that C5L2-deficient mice are protected from the development of airway hyperresponsiveness, Th2 cytokine production, eosinophilic airway inflammation, serum IgE, or mucus production. Surprisingly, HDM-induced experimental asthma in C5L2-deficient mice was associated with increased pulmonary IL-17A production and increased airway neutrophil numbers. To directly assess the role of C5L2 on myeloid dendritic cells (mDCs) during allergen sensitization, we performed single or repeated adoptive transfers of C5L2-deficient mDCs into wild-type mice. HDM-pulsed C5L2-deficient mDCs induced strong Th2 cytokine production, which was associated with marked IFN-γ and IL-17A production, decreased eosinophil numbers, and reduced IgE production as compared with HDM-pulsed mDCs from wild-type mice. HDM stimulation of C5L2(-/-) mDCs in vitro resulted in production of Th17-promoting cytokine IL-23, which was absent in wild-type mDCs. Our findings suggest that C5L2 acts at the mDC/T cell interface to control the development of Th1 and Th17 cells in response to airway HDM exposure. Furthermore, it drives Th2 immune responses independent of mDCs, suggesting a complex role for C5L2 in the development of experimental allergic asthma.

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    • "Mediators of Inflammation artery disease [14] [15]. Accumulating evidence demonstrates direct interactions between C5L2 and C5aR [16], and this has been implicated in inflammatory conditions such as sepsis [13] [17]. "
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    • "It also may act as a negative modulator of C5aR-mediated signal transduction through the β-arrestin pathway.27 However, recent studies have suggested that C5L2 has a proinflammatory role in experimental sepsis,28 allergic asthma,29 and also may control the development of T-helper 17 cells that are essential in asthma30 as well as autoimmune arthritis.31 "
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    • "This lack of signaling together with its constitutive recycling and the internalization of its ligands suggests that C5L2 is a decoy receptor regulating the bioavailability of C5a/C5adesArg, thereby limiting C5aR-dependent cell activation. In addition to its decoy functions, several studies provide evidence that C5L2 exerts signaling properties independent of G-protein activation and regulates systemic inflammatory diseases including allergic asthma and sepsis (Chen et al., 2007; Rittirsch et al., 2008; Zhang et al., 2010). A role for C5a in CD4 + T cell regulation has first been considered when it was shown that C5a inhibits IL-12 production from human monocytes and monocyte-derived DCs (Braun et al., 2000; Wittmann et al., 1999) in response to bacterial challenge in vitro. "
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