Abstract
C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1). Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs) during the allergic effector phase using a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we determined the role of C5aR1 signaling in neutrophils, moDCs and macrophages for the pulmonary recruitment of such cells and the importance of C5aR1-mediated activation of LysM-expressing cells for the development of allergic asthma. We used LysM-C5aR1 KO mice with a specific deletion of C5aR1 in LysMCre-expressing cells and confirmed the specific deletion of C5aR1 in neutrophils, macrophages and moDCs in the airways and/or the lung tissue. We found that alveolar macrophage numbers were significantly increased in LysM-C5aR1 KO mice. Induction of ovalbumin (OVA)-driven experimental allergic asthma in GFP-C5aR1fl/fl and LysM-C5aR1 KO mice resulted in strong but similar airway resistance, mucus production and Th2/Th17 cytokine production. In contrast, the number of airway but not of pulmonary neutrophils was lower in LysM-C5aR1 KO as compared with GFP-C5aR1fl/fl mice. The recruitment of macrophages, cDCs, moDCs, T cells and type 2 innate lymphoid cells was not altered in LysM-C5aR1 KO mice. Our findings demonstrate that C5aR1 is critical for steady state control of alveolar macrophage numbers and the transition of neutrophils from the lung into the airways in OVA-driven allergic asthma. However, C5aR1 activation of LysM-expressing cells plays a surprisingly minor role in the recruitment and activation of such cells and the development of the allergic phenotype in OVA-driven experimental allergic asthma.
Highlights
Allergic asthma is a chronic pulmonary disease which manifests as an inappropriate immune response to aeroallergens in susceptible individuals
green fluorescent protein (GFP)-C5a receptor 1 (C5aR1) is conditionally deleted in pulmonary neutrophils, macrophages and dendritic cell (DC) but not in eosinophils
We observed that, at steady state, LysM-C5aR1 KO airway and tissue-associated alveolar macrophages (AMs), but not eosinophils were negative for GFP (Fig 1A), indicating that LysM+ pulmonary cells lost the expression of C5aR1
Summary
Allergic asthma is a chronic pulmonary disease which manifests as an inappropriate immune response to aeroallergens in susceptible individuals. Allergic asthma is characterized by a Th2/ Th17 maladaptive immune response. C5a exerts dual functions during the sensitization and the effector phase of allergic asthma [1, 2]. The C5a/C5aR1 signaling axis has been identified as a main regulator of dendritic cell (DC) functions and the development of maladaptive Th2/Th17 immune responses [4, 5]. PDCs can suppress myeloid dendritic cell functions by a C5aR1-dependent mechanism [2, 6]. A recent study using a GFP-C5aR1 knock-in mouse demonstrated that C5aR1 expression is regulated in several innate immune cells that play important roles for the development of the allergic phenotype during the effector phase. C5aR1 expression was downregulated in airway and tissue alveolar macrophages, CD11b+ conventional (c)DCs and monocyte-derived (mo) DCs but upregulated in eosinophils in an OVA-induced allergic asthma experimental model using GFP-C5aR1fl/fl mice [8]
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