Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Research Center of Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Biomed Pharmacother. 2021 May;137:111365. doi: 10.1016/j.biopha.2021.111365. Epub 2021 Feb 12.
Defective absorption of acute allergic airway inflammation is involved in the initiation and development of chronic asthma. After allergen exposure, there is a rapid recruitment of macrophages around the airways, which promote acute inflammatory responses. The Ang-(1-7)/Mas receptor axis reportedly plays protective roles in various tissue inflammation and remodeling processes in vivo. However, the exact role of Mas receptor and their underlying mechanisms during the pathology of acute allergic airway inflammation remains unclear.
We investigated the role of Mas receptor in acute allergic asthma and explored its underlying mechanisms in vitro, aiming to find critical molecules and signal pathways.
Mas receptor expression was assessed in ovalbumin (OVA)-induced acute asthmatic murine model. Then we estimated the anti-inflammatory role of Mas receptor in vivo and explored expressions of several known inflammatory cytokines as well as phosphorylation levels of MAPK pathways. Mas receptor functions and underlying mechanisms were studied further in the human bronchial epithelial cell line (16HBE).
Mas receptor expression decreased in acute allergic airway inflammation. Multiplex immunofluorescence co-localized Mas receptor and EpCAM, indicated that Mas receptor may function in the bronchial epithelium. Activating Mas receptor through AVE0991 significantly alleviated macrophage infiltration in airway inflammation, accompanied with down-regulation of CCL2 and phosphorylation levels of MAPK pathways. Further studies in 16HBE showed that AVE0991 pre-treatment inhibited LPS-induced or anisomycin-induced CCL2 increase and THP-1 macrophages migration via JNK pathways.
Our findings suggested that Mas receptor activation significantly attenuated CCL2 dependent macrophage recruitments in acute allergic airway inflammation through JNK pathways, which indicated that Mas receptor, CCL2 and phospho-JNK could be potential targets against allergic airway inflammation.
急性过敏性气道炎症的吸收缺陷参与了慢性哮喘的发生和发展。在过敏原暴露后，气道周围迅速募集巨噬细胞，促进急性炎症反应。已有报道称，血管紧张素 1-7（Ang-(1-7)）/Mas 受体轴在体内各种组织炎症和重塑过程中发挥保护作用。然而，Mas 受体在急性过敏性气道炎症发病机制中的确切作用及其潜在机制仍不清楚。
我们研究了 Mas 受体在急性过敏性哮喘中的作用，并在体外探索其潜在机制，旨在寻找关键分子和信号通路。
在卵清蛋白（OVA）诱导的急性哮喘小鼠模型中评估 Mas 受体的表达。然后，我们评估了 Mas 受体在体内的抗炎作用，并研究了几种已知炎症细胞因子的表达以及 MAPK 通路的磷酸化水平。进一步在人支气管上皮细胞系（16HBE）中研究 Mas 受体的功能及其潜在机制。
Mas 受体在急性过敏性气道炎症中表达下调。多重免疫荧光共定位显示 Mas 受体与 EpCAM 共定位，提示 Mas 受体可能在支气管上皮细胞中发挥作用。通过 AVE0991 激活 Mas 受体可显著减轻气道炎症中的巨噬细胞浸润，同时下调 CCL2 和 MAPK 通路的磷酸化水平。在 16HBE 中的进一步研究表明，AVE0991 预处理可通过 JNK 通路抑制 LPS 诱导或放线菌酮诱导的 CCL2 增加和 THP-1 巨噬细胞迁移。
我们的研究结果表明，Mas 受体激活通过 JNK 通路显著减轻急性过敏性气道炎症中 CCL2 依赖的巨噬细胞募集，提示 Mas 受体、CCL2 和磷酸化 JNK 可能是针对过敏性气道炎症的潜在靶点。
