Immunoregulatory Roles of the Anaphylatoxin Receptors in Experimental Allergic Asthma PDF Download

Author: Xun Zhang
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Languages : en
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Book Description
The complement anaphylatoxins (ATs) C3a and C5a are proinflammatory mediators contributing to the effector phase of allergic asthma. Recent studies suggest that ATs also play important immunoregulatory roles during allergen sensitization particularly at the interface of dendritic cells (DCs) and T cells. ATs exert their biological activities through interaction with three cognate receptors, namely the C3a receptor (C3aR), C5aR and C5a receptor-like 2 (C5L2). To investigate AT receptor-mediated regulation of pulmonary inflammation and maladaptive immunity, we have determined the immune responses in C3aR-, C5aR- and C5L2-deficient mice in models of house dust mite (HDM)- and ovalbumin (OVA)-induced experimental allergic asthma. Further, we directly examined the impact of AT receptor signaling in myeloid DCs (mDCs) on T cell activation and subsequent development of asthmatic phenotype. We found that HDM-treated C5aR-deficient mice (C5aRKOs) exhibited strong airway hyperresponsiveness (AHR), airway eosinophilia and dysregulated adaptive T and B cell responses, suggesting a protective immunoregulatory role for C5a in response to allergen exposure. Surprisingly, we observed that bone marrow-derived C5aR-deficient mDCs had an impaired ability to drive T helper type 2 (Th2) immunity, AHR and airway inflammation when adoptively transferred into the airways of naïve wild type (WT) mice. These data suggest that C5aR signaling in mDCs is required for efficient mDC function to activate naïve T cells and mediate allergen-induced inflammatory responses. Our findings further demonstrate that C5aR signaling in cell types other than mDCs accounts for its protective effect. Indeed, we found that C5aR signaling is required for pulmonary accumulation of tolerogenic plasmacytoid DCs expressing inhibitory B7-H1 and B7-DC molecules as a means to control Th2 cell effector functions. Contrary to C5aRKOs, C3aRKO and C5L2KO mice showed attenuated allergic phenotypes in response to inhaled allergens. Importantly, C5aR blockade in C3aRKOs resulted in a strong allergic phenotype similar to C5aRKOs. Further, we found reciprocal modulation of C5aR and C3aR in pulmonary DCs suggesting that C3aR signaling enhances the development of airway inflammation and maladaptive Th2 immunity indirectly through regulation of protective C5aR signaling. Interestingly, we observed that HDM-pulsed C3aR-deficient mDCs had the same potency as WT mDCs to drive Th2 immune responses, suggesting that C3aR signaling is not required for mDC-mediated activation of naïve T cells but important for proinflammatory effector functions mediated through infiltrating inflammatory cells during the allergic effector phase. In contrast, C5L2 and C5aR synergistically activated mDCs as evidenced by an impaired ability of C5L2-deficient mDCs to promote AHR, airway eosinophilia and B cell responses. Furthermore, we found a marked increase in pulmonary production of interferon-gamma and interleukin-17 associated with substantial airway neutrophilia in mice receiving C5aR- or C5L2-deficient mDCs, suggesting that C5a controls the differentiation of Th1 and Th17 cells as a potential mechanism to enhance Th2 cell development. In summary, our data presented in this thesis suggest that AT receptors exert critical and complex immunoregulatory functions that either promote or suppress the development of allergic asthma through regulation of DC-T cell interactions, effector cell and possibly pulmonary resident cell activities.