在哮喘模型中PM2.5可以通过Got1 and HIF-1α扰乱Th17和Treg的平衡
2019/11/12
摘要
背景: 流行病学证据表明暴露于颗粒物≤2.5μm (PM2.5)加重哮喘。
目的: PM2.5暴露与哮喘严重程度之间的潜在机制。
方法: 在CD4+ T细胞特异性芳基烃受体(AhR)缺失小鼠哮喘模型中，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逆转录聚合酶链反应研究了PM2.5和多环芳烃(PAHs)对T-helper 17/T-regulatory (Th17/Treg)细胞分化的影响。通过mRNA测序、染色质免疫沉淀、亚硫酸氢盐测序和糖酵解率研究机制。
结果: PM2.5对Treg细胞的分化有抑制作用，促进Th17细胞的分化，并以ahr依赖的方式加重哮喘。PM2.5和它的一个主要多环芳烃, 茚(1、2、3 cd)芘(IP)通过AhRs上调低氧诱导因子HIF-α的表达和增强糖酵解来促进Th17细胞的分化。暴露于PM2.5和IP可通过AhRs和R-2-羟基戊二酸积累增强谷氨酸草酰乙酸转氨酶(Got)1的表达，抑制10，11转位甲基胞嘧啶二氧合酶-2的活性，导致Foxp3位点的高甲基化，影响Treg细胞的分化。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细胞中也发现了PM2.5或IP暴露对Th17/Treg失衡的类似调节作用，在病例对照设计中，多环芳烃暴露似乎是哮喘的潜在危险因素。
结论: 分子通路AhR-HIF-1α和AhR-Got1调解肺反应在暴露PM2.5通过干扰Th17 / Treg细胞的平衡。
Sun L, Fu J, Lin SH, Sun JL, Xia L, Lin CH, Liu L, Zhang C, Yang L, Xue P, Wang X, Huang S, Han X, Chen HL, Huang MS, Zhang X, Huang SK, Zhou Y.
Abstract
BACKGROUND: Epidemiologic evidence suggests that exposure to particulate matter ≤2.5 μm (PM2.5) aggravates asthma.
OBJECTIVE: 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 T-helper 17/T-regulatory (Th17/Treg) cells were investigated by flow cytometry and quantitative reverse-transcription polymerase chain reaction. Mechanisms were investigated by 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 up-regulating hypoxia-inducible factor-1α expression and enhancing glycolysis via AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase (Got)1 expression via AhRs and accumulation of R-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 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 molecular pathways AhR-HIF-1α and AhR-Got1 mediate pulmonary responses upon exposure to PM2.5 through their ability to disturb the balance of Th17/Treg cells.
背景: 流行病学证据表明暴露于颗粒物≤2.5μm (PM2.5)加重哮喘。
目的: PM2.5暴露与哮喘严重程度之间的潜在机制。
方法: 在CD4+ T细胞特异性芳基烃受体(AhR)缺失小鼠哮喘模型中，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逆转录聚合酶链反应研究了PM2.5和多环芳烃(PAHs)对T-helper 17/T-regulatory (Th17/Treg)细胞分化的影响。通过mRNA测序、染色质免疫沉淀、亚硫酸氢盐测序和糖酵解率研究机制。
结果: PM2.5对Treg细胞的分化有抑制作用，促进Th17细胞的分化，并以ahr依赖的方式加重哮喘。PM2.5和它的一个主要多环芳烃, 茚(1、2、3 cd)芘(IP)通过AhRs上调低氧诱导因子HIF-α的表达和增强糖酵解来促进Th17细胞的分化。暴露于PM2.5和IP可通过AhRs和R-2-羟基戊二酸积累增强谷氨酸草酰乙酸转氨酶(Got)1的表达，抑制10，11转位甲基胞嘧啶二氧合酶-2的活性，导致Foxp3位点的高甲基化，影响Treg细胞的分化。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细胞中也发现了PM2.5或IP暴露对Th17/Treg失衡的类似调节作用，在病例对照设计中，多环芳烃暴露似乎是哮喘的潜在危险因素。
结论: 分子通路AhR-HIF-1α和AhR-Got1调解肺反应在暴露PM2.5通过干扰Th17 / Treg细胞的平衡。
(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. 2019 Oct 21. pii: S0091-6749(19)31329-6. doi: 10.1016/j.jaci.2019.10.008)
(J Allergy Clin Immunol. 2019 Oct 21. pii: S0091-6749(19)31329-6. doi: 10.1016/j.jaci.2019.10.008)
PM2.5 disturbs the balance of Th17/Treg cells by targeting Got1 and HIF-1α in an asthma model.
Sun L, Fu J, Lin SH, Sun JL, Xia L, Lin CH, Liu L, Zhang C, Yang L, Xue P, Wang X, Huang S, Han X, Chen HL, Huang MS, Zhang X, Huang SK, Zhou Y.
Abstract
BACKGROUND: Epidemiologic evidence suggests that exposure to particulate matter ≤2.5 μm (PM2.5) aggravates asthma.
OBJECTIVE: 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 T-helper 17/T-regulatory (Th17/Treg) cells were investigated by flow cytometry and quantitative reverse-transcription polymerase chain reaction. Mechanisms were investigated by 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 up-regulating hypoxia-inducible factor-1α expression and enhancing glycolysis via AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase (Got)1 expression via AhRs and accumulation of R-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 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 molecular pathways AhR-HIF-1α and AhR-Got1 mediate pulmonary responses upon exposure to PM2.5 through their ability to disturb the balance of Th17/Treg cells.
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