在哮喘模型中，直径≤2.5um的颗粒物通过靶向谷氨酸草酰乙酸转氨酶1和缺氧诱导因子1α来扰乱TH17/调节性T细胞的平衡
2020/12/17
摘要
背景：流行病学证据表明，暴露于直径≤2.5um的颗粒物（PM2.5）会加重哮喘。目的：我们试图调查PM2.5暴露与哮喘严重程度之间的潜在机制。
方法：采用CD4+T细胞特异性芳香烃受体（AhR）阴性小鼠哮喘模型，研究PM2.5暴露与哮喘严重程度的关系。采用流式细胞术和定量RT-PCR方法研究PM2.5和多环芳烃（PAHs）对TH17/Treg细胞分化的影响。通过使用mRNA测序、染色质免疫沉淀、亚硫酸氢盐测序和糖酵解速率来研究机制。
结果：PM2.5以AhR依赖性方式损害Treg细胞分化，促进TH17细胞分化，加重哮喘。PM2.5及其突出的PAHs之一茚并[1,2,3-cd]芘（IP）通过上调缺氧诱导因子1α的表达并通过AhRs增强糖酵解，促进Th17细胞的分化。PM2.5和IP暴露通过AhRs和2-羟基戊二酸蓄积增强谷氨酸草酰乙酸转氨酶1（Got1）表达，抑制了10-11易位甲基胞嘧啶双加氧酶2活性，导致转录因子叉头框P3位点高甲基化，Treg细胞分化受损。一种Got1抑制剂（氨基氧基）乙酸，通过改变TH17细胞向Treg细胞的分化来改善哮喘。在人类T细胞中观察到暴露于PM2.5或IP对TH17/Treg细胞失衡的类似调节作用，并在病例对照设计中，PAH暴露似乎是哮喘的潜在风险因素。
结论：AhR-缺氧诱导因子1α和AhR-GOT1分子通路通过干扰TH17/Treg细胞平衡介导PM2.5暴露的肺部反应。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2020 Jan;145(1):402-414. doi: 10.1016/j.jaci.2019.10.008.)
(J Allergy Clin Immunol. 2020 Jan;145(1):402-414. doi: 10.1016/j.jaci.2019.10.008.)
Particulate matter of 2.5 μm or less in diameter disturbs the balance of T H 17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model
Licheng Sun, Jinrong Fu , Sheng-Hao Lin , Jin-Lyu Sun , Li Xia , Ching-Hsiung Lin , Lijuan Liu , Caiyan Zhang , Lan Yang , Ping Xue , Xiang Wang, Saihua Huang , Xiao Han , Hua-Ling Chen, Ming-Shyan Huang , Xiaobo Zhang , Shau-Ku Huang , Yufeng Zhou
Abstract
Background: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 μm or less in diameter (PM2.5) aggravates asthma.
Objective: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity.
Methods: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell-specific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates.
Results: PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma.
Conclusions: The AhR-hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.
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Foxp3+调节T细胞通过miR-342依赖的机制调节糖皮质激素的抗炎作用
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调节性B细胞控制鼠哮喘模型中气道高反应性和肺部重塑
