Licheng Sun1, Jinrong Fu2, Sheng-Hao Lin3, Jin-Lyu Sun4, Li Xia1, Ching-Hsiung Lin3, Lijuan Liu5, Caiyan Zhang1, Lan Yang1, Ping Xue6, Xiang Wang6, Saihua Huang1, Xiao Han1, Hua-Ling Chen7, Ming-Shyan Huang8, Xiaobo Zhang5, Shau-Ku Huang9, Yufeng Zhou10. 1. Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Neonatal Diseases (Fudan University), Shanghai, China. 2. Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Respirology Department, Children's Hospital of Fudan University, Shanghai, China. 3. Chest Division, Department of Internal Medicine, Chang-Hua Christian Hospital, Chang-Hua, Taiwan. 4. Department of Allergy, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, Beijing, China. 5. Respirology Department, Children's Hospital of Fudan University, Shanghai, China. 6. Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. 7. National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. 8. Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. 9. National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Johns Hopkins University School of Medicine, Baltimore, Md; Kaohsiung Medical University, Kaohsiung, Taiwan; Lou-Hu Hospital, Shen-Zhen University, Shen-Zhen, China. 10. Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; NHC Key Laboratory of Neonatal Diseases (Fudan University), Shanghai, China. Electronic address: yfzhou1@fudan.edu.cn.
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.
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.
Authors: J A Tuazon; B Kilburg-Basnyat; L M Oldfield; R Wiscovitch-Russo; K Dunigan-Russell; A V Fedulov; K J Oestreich; K M Gowdy Journal: Curr Allergy Asthma Rep Date: 2022-04-08 Impact factor: 4.919