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

ABSTRACT 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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Available from: Jörg Köhl, Sep 26, 2015
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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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    ABSTRACT: Adipose tissue receptors C5aR and C5L2 and their heterodimerization/functionality and interaction with ligands C5a and acylation stimulating protein (ASP) have been evaluated in cell and rodent studies. Their contribution to obesity factors in humans remains unclear. We hypothesized that C5a receptors, classically required for host defense, are also associated with adiposity. Anthropometry and fasting blood parameters were measured in 136 women divided by body mass index (BMI): normal/overweight (≤30 kg/m(2); n = 34), obese I (≤45 kg/m(2); n = 33), obese II (≤51 kg/m(2); n = 33), and obese III (≤80 kg/m(2); n = 36). Subcutaneous and omental adipose tissue C5aR and C5L2 expression were analysed. C5L2 expression was comparable between subcutaneous and omental across all BMI groups. Plasma ASP and ASP/omental C5L2 expression increased with BMI (P < 0.001 and P < 0.01, resp.). While plasma C5a was unchanged, C5aR expression decreased with increasing BMI in subcutaneous and omental tissues (P < 0.01 and P < 0.05, resp.), with subcutaneous omental depots. Omental C5L2/C5aR ratio increased with BMI (P < 0.01) with correlations between C5L2/C5aR and waist circumference, HDL-C, and adiponectin. Tissue and BMI differences in receptors and ligands, particularly in omental, suggest relationship to metabolic disturbances and highlight adipose-immune interactions.
    Mediators of Inflammation 01/2014; 2014(4):413921. DOI:10.1155/2014/413921 · 3.24 Impact Factor
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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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    ABSTRACT: Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex-mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.
    Seminars in Nephrology 11/2013; 33(6):479-92. DOI:10.1016/j.semnephrol.2013.08.001 · 3.48 Impact Factor
    • "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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    ABSTRACT: Complement receptors are expressed on cells of the innate and the adaptive immune system. They play important roles in pathogen and danger sensing as they translate the information gathered by complement fluid phase sensors into cellular responses. Further, they control complement activation on viable and apoptotic host cells, clearance of immune complexes and mediate opsonophagocytosis. More recently, evidence has accumulated that complement receptors form a complex network with other innate receptors systems such as the Toll-like receptors, the Notch signaling system, IgG Fc receptors and C-type lectin receptors contributing to the benefit and burden of innate and adaptive immune responses in autoimmune and allergic diseases as well as in cancer and transplantation. Here, we will discuss recent developments and emerging concepts of complement receptor activation and regulation with a particular focus on the differentiation, maintenance and contraction of effector and regulatory T cells.
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