PM2.5 Exposure Induces Inflammatory Response in Macrophages via the TLR4/COX-2/NF-κB Pathway
PM2.5 Exposure Induces Inflammatory Response in Macrophages via the TLR4/COX-2/NF-κB Pathway
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PM2.5 暴露通过 TLR4/COX-2/NF-kappa B 途径诱导巨噬细胞炎症反应
DOI：
10.1007/s10753-020-01269-y
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发表时间：
2020-06-05
期刊：
影响因子：
5.1
通讯作者：
Ding, Zhishan
中科院分区：
文献类型：
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作者：
Fu, Huiying;Liu, Xia;Ding, Zhishan
空气动力学直径小于2.5微米的细颗粒物(PM2.5)是一种严重的空气污染物，与健康问题有关。巨噬细胞在PM2.5诱导的呼吸道疾病炎症过程中起重要作用。然而，具体的机制仍不清楚。我们的目的是研究PM2.5诱导炎症的机制，并寻找可能的抗炎抑制剂。在杭州、中国采集了PM2.5，对吸附在PM2.5上的物质组成进行了表征。RAW 254.7细胞随后被PM2.5处理。通过高水平单核细胞趋化蛋白-1(MCP-1)、肿瘤坏死因子-α(TNF-α)和白介素6(IL-6)的释放以及诱导型一氧化氮合酶(INOS)和肿瘤坏死因子-α(TNF-α)mRNA表达的增加，观察到巨噬细胞吞噬功能，并触发炎症反应。经典抑制剂的治疗以剂量依赖的方式抑制了释放的促炎因子。利用免疫炎症化合物文库，我们筛选了70个抑制剂，并根据它们的抑制作用的相似性进行了聚类，并用细胞检测珠阵列法(CBA)进行了检测。分子分析显示，在PM2.5刺激的RAW 254.7细胞中，Toll样受体4、核因子kappaB和环氧合酶2的表达增加。选择相应的抑制物，用CBA法验证其抗炎作用。这些抑制剂减少了促炎因子的表达，这种减少与TLR4/NF-kappa B/COX-2信号通路的下调有关。综上所述，PM2.5通过激活TLR4/NF-kappa B/COX-2信号通路诱导巨噬细胞的炎症反应，该通路的抑制剂有望成为治疗炎症性疾病的候选药物。
Fine particulate matter with an aerodynamic diameter less than 2.5 mu m (PM2.5) is a serious air pollutant associated with health problems. Macrophages play an important role in the process of PM2.5-induced inflammation in respiratory diseases. However, the detailed mechanism remains unclear. We aimed to examine the mechanism of PM2.5-induced inflammation and find possible anti-inflammatory inhibitors. PM2.5 was collected in Hangzhou, China, and the composition of adsorbed materials on PM2.5 was characterized. RAW 254.7 cells were then treated with PM2.5. Phagocytosis was observed, and inflammatory response was triggered as demonstrated by the release of high levels of monocyte chemoattractant protein-1(MCP-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) and increased mRNA expression of inducible nitric oxide synthase (iNOS) and TNF-alpha. Treatment with classic inhibitors suppressed the released pro-inflammatory factors in a dose-dependent manner. Using Immunology Inflammation Compound Library, we screened 70 inhibitors and clustered them based on similarities in their inhibitory effects, which we detected using cytometric bead array (CBA) assay. Molecular analysis revealed that the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-kappa B), and cyclooxygenase-2 (COX-2) was increased in PM2.5-stimulated RAW 254.7 cells. Corresponding inhibitors were selected, and the CBA assay verified their anti-inflammatory effects. These inhibitors reduced the expression of pro-inflammatory factors, and this reduction was correlated with the downregulation of the TLR4/NF-kappa B/COX-2 signaling pathway. In conclusion, PM2.5 induces an inflammatory response in macrophages via activation of TLR4/NF-kappa B/COX-2 signaling, and the inhibitors of this pathway are potential therapeutic candidates to treat inflammatory disorders.