Ender Fanny, Wiese Anna V, Schmudde Inken, Sun Jing, Vollbrandt Tillman, König Peter, Laumonnier Yves, Köhl Jörg
Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
Institute for Anatomy, University of Lübeck, Lübeck, Germany.
PLoS One. 2017 Feb 23;12(2):e0172446. doi: 10.1371/journal.pone.0172446. eCollection 2017.
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.
C5a在过敏性哮喘的效应阶段主要通过激活C5a受体1(C5aR1)来驱动气道收缩和炎症。然而,在过敏性效应阶段,髓系和淋巴细胞上C5aR1的表达尚不明确。最近,我们构建并鉴定了一种带有绿色荧光蛋白(GFP)的C5aR1条件性敲入小鼠。在此,我们使用该报告菌株监测卵清蛋白(OVA)诱导的过敏性哮喘效应阶段气道、肺和淋巴结细胞中C5aR1的表达。C5aR1报告基因小鼠和野生型小鼠表现出相似的过敏表型,气道阻力、黏液分泌、嗜酸性粒细胞/中性粒细胞气道炎症以及Th2/Th17细胞因子产生相当。在过敏性效应阶段,肺组织嗜酸性粒细胞中C5aR1表达增加,但气道和肺巨噬细胞以及肺CD11b⁺传统树突状细胞(cDC)和单核细胞衍生树突状细胞(moDC)中C5aR1表达降低。令人惊讶的是,中性粒细胞中的表达不受影响。值得注意的是,OVA激发后,纵隔淋巴结(mLN)中的moDC而非CD11b⁺ cDC表达的C5aR1比肺中的DC少。最后,在过敏条件下,CD103⁺ cDC以及Th2或Th17分化的CD4⁺ T细胞、B细胞或2型固有淋巴细胞(ILC2)等淋巴谱系细胞均不表达C5aR1。我们的研究结果表明,小鼠气道、肺组织和mLN中C5aR1存在复杂的调控模式,提示在过敏性哮喘实验模型中,C5a/C5aR1轴通过激活所有三个区域的髓系细胞来控制气道收缩和炎症。
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