Abstract
C5a drives airway constriction and inflammation during the effector phase of allergic asthma, mainly through the activation of C5a receptor 1 (C5aR1). Yet, C5aR1 expression on myeloid and lymphoid cells during the allergic effector phase is ill-defined. Recently, we generated and characterized a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse. Here, we used this reporter strain to monitor C5aR1 expression in airway, pulmonary and lymph node cells during the effector phase of OVA-driven allergic asthma. C5aR1 reporter and wildtype mice developed a similar allergic phenotype with comparable airway resistance, mucus production, eosinophilic/neutrophilic airway inflammation and Th2/Th17 cytokine production. During the allergic effector phase, C5aR1 expression increased in lung tissue eosinophils but decreased in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs). Surprisingly, expression in neutrophils was not affected. Of note, moDCs but not CD11b+ cDCs from mediastinal lymph nodes (mLN) expressed less C5aR1 than DCs residing in the lung after OVA challenge. Finally, neither CD103+ cDCs nor cells of the lymphoid lineage such as Th2 or Th17-differentiated CD4+ T cells, B cells or type 2 innate lymphoid cells (ILC2) expressed C5aR1 under allergic conditions. Our findings demonstrate a complex regulation pattern of C5aR1 in the airways, lung tissue and mLN of mice, suggesting that the C5a/C5aR1 axis controls airway constriction and inflammation through activation of myeloid cells in all three compartments in an experimental model of allergic asthma.
Highlights
Allergic asthma is one of the most prevalent diseases of the western world
Using floxed green fluorescent protein (GFP)-C5a receptor 1 (C5aR1) reporter mice, we recently described C5aR1 expression in lung neutrophils, eosinophils, macrophages, CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs) but not in CD103+ cDCs under steady
Upon OVA stimulation, we observed a strong recruitment of neutrophils, eosinophils and lymphocytes into the bronchoalveolar compartment in both, WT and GFP-C5aR1flox/flox mice
Summary
Allergic asthma is one of the most prevalent diseases of the western world. It develops in genetically susceptible individuals as a chronic inflammatory disorder of the upper airways leading. It is well appreciated that the complement cleavage product C5a regulates development of allergic asthma during allergen sensitization and the effector phase [5]. More sophisticated gating strategies were used to phenotypically characterize pulmonary immune cell subsets [13, 14] allowing a better mapping of C5aR1 expression in lung DC populations [15]. While the expression pattern of C5aR1 in pulmonary cells at steady state is relatively clear, the regulation of C5aR1 expression under allergic asthma conditions during the effector phase remains elusive. We used WT and floxed GFP-C5aR1 reporter mice (GFPC5aR1flox/flox) [15] in a model of OVA-driven allergic asthma and assessed C5aR1 expression in myeloid and lymphoid cells isolated from the airways, lung tissue and mLN. Our data demonstrate that C5aR1 is expressed and differentially regulated in the myeloid but not in the lymphoid compartment
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