Acetyl CoA carboxylase promotes airway inflammation of asthma by inducing Th17 development_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZHU Fangfang , CAO Huan , HE Guangzhen , WANG Yimin , CHEN Yifei , YANG Jiong ,  GAO Yadong

Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P. R. China;

Corresponding author：

GAO Yadong, Email: gaoyadong@whu.edu.cn

Keywords：

Asthma; Acetyl CoA carboxylase; Th17 cells; TOFA

DOI：

10.7507/1671-6205.201703001

Video：

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ObjectiveTo investigate the role of acetyl CoA carboxylase (ACC)-induced Th17 development in the pathogenesis of asthma.MethodsA total of 24 C57BL/6 mice were randomly assigned to 4 groups (6 in each group), namely a normal group, an asthma group, a DMSO control group and an ACC inhibitor group. The mice in the asthma group, the DMSO control group and the ACC inhibitor group were sensitized and challenged with ovalbumin (OVA) to establish a model of acute asthma, the mice in the normal group were administrated with equal volume of phosphate buffered saline (PBS). The mice in the ACC inhibitor group were intraperitoneally administrated with TOFA, an ACC inhibitor (dissolved in DMSO firstly, then diluted with PBS solution) twice a week, while the DMSO control group were intraperitoneally administrated with equal concentration of DMSO. All mice were sacrificed 24 days later, then lung tissue and serum were collected. The inflammatory cells infiltrated in lung tissue were assessed by the means of HE staining under light microscope. The total level of IgE in serum was detected by ELISA. The percentage of Th17 cells in CD4⁺ T cells in lung tissue was evaluated by flow cytometry.ResultsThe inflammatory cells infiltration in the asthma group, the DMSO control group and the ACC inhibitor group increased significantly compared with that of the normal group (3.50±0.14, 3.47±0.08, 2.07±0.20vs. 0.50±0.17, allP<0.001), but there were no significant differences between the DMSO control group group and the asthma group (P>0.05), while administration of TOFA could significantly decrease the inflammatory cells infiltration (P<0.001). The total level of serum IgE in the asthma group, the DMSO control group and the ACC inhibitor group was significantly higher than that in the normal group [(5 680.40±831.40) ng/ml, (5 624.79±365.50) ng/ml, (2 028.95±134.60) g/mlvs. (400.52±57.13) ng/ml, allP<0.008], but there were no significant differences between the DMSO control group and the asthma group (P>0.05), while the total level of serum IgE in the ACC inhibitor group was significantly lower than that in the asthma group (P<0.008). The percentage of Th17 cells in CD4⁺ T cells in lung tissue increased markedly in the asthma group, the DMSO control group and the ACC inhibitor group compared with the normal group [(2.01±0.12)%, (1.95±0.16)%, (0.82±0.04)%vs. (0.59±0.03)%, bothP<0.008], and also there were no significant differences between the DMSO control group and the asthma group (P>0.05), while administration of TOFA could notably reduce the percentage of Th17 cells (P<0.008).ConclusionInhibition of ACC significantly alleviates the airway inflammation of OVA-induced asthma, and reduces the percentage of Th17 cells in lung tissue and the total level of serum IgE. ACC may participate in the pathogenesis of asthma by inducing Th17 development.

Citation： ZHU Fangfang, CAO Huan, HE Guangzhen, WANG Yimin, CHEN Yifei, YANG Jiong, GAO Yadong. Acetyl CoA carboxylase promotes airway inflammation of asthma by inducing Th17 development. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(5): 500-504. doi: 10.7507/1671-6205.201703001 Copy

1.	Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol, 2015, 16(1): 45-56.
2.	Kujur W, Gurram RK, Haleem N, et al. Caerulomycin A inhibits Th2 cell activity: a possible role in the management of asthma. Sci Rep, 2015, 5: 15396.
3.	梁振宇, 蔡绍曦, 赵海金. 哮喘的临床与炎症表型. 中国呼吸与危重监护杂志, 2010, 9(5): 546-548.0.
4.	Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol, 2013, 25(6): 755-760.
5.	李贱, 邹朋成, 杨莉容等. Th17 细胞在哮喘发病中的作用研究进展. 中国呼吸与危重监护杂志, 2013, 12(3): 322-324.0.
6.	Kudo M, Melton AC, Chen C, et al. IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med, 2012, 18(4): 547-554.
7.	Lajoie S, Lewkowich IP, Suzuki Y, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol, 2010, 11(10): 928-935.
8.	Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?. Respir Res, 2006, 7: 135.
9.	Finkelman FD, Hogan SP, Hershey GK, et al. Importance of cytokines in murine allergic airway disease and human asthma. J Immunol, 2010, 184(4): 1663-1674.
10.	Ma C, Ma Z, Fu Q, et al. Curcumin attenuates allergic airway inflammation by regulation of CD4⁺CD25⁺ regulatory T cells (Tregs) /Th17 balance in ovalbumin-sensitized mice. Fitoterapia, 2013, 87: 57-64.
11.	Park BS, Hong GU, Ro JY. Foxp3(+)-Treg cells enhanced by repeated low-dose gamma-irradiation attenuate ovalbumin-induced allergic asthma in mice. Radiat Res, 2013, 179(5): 570-583.
12.	周辰, 陈军浩, 殷凯生. 辅助性 T 细胞 17 和调节性 T 细胞在哮喘小鼠中的失衡表达及其意义. 中国呼吸与危重监护杂志, 2010, 9(1): 28-31.0.
13.	Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med, 2014, 20(11): 1327-1333.
14.	Yoshioka M, Sagara H, Takahashi F, et al. Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation. Am J Physiol Lung Cell Mol Physiol, 2009, 296(1): L30-L36.
15.	Svensson RU, Parker SJ, Eichner LJ, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med, 2016, 22(10): 1108-1119.
16.	Rodrigues HG, Takeo Sato F, Curi R, et al. Fatty acids as modulators of neutrophil recruitment, function and survival. Eur J Pharmacol, 2016, 785: 50-58.
17.	Rehman A, Hemmert KC, Ochi A, et al. Role of fatty-acid synthesis in dendritic cell generation and function. J Immunol, 2013, 190(9): 4640-4649.
18.	Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol, 2015, 36(2): 81-91.
19.	Moon JS, Lee S, Park MA, et al. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest, 2015, 125(2): 665-680.
20.	Endo Y, Asou HK, Matsugae N, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep, 2015, 12(6): 1042-1055.
21.	Ano S, Morishima Y, Ishii Y, et al. Transcription factors GATA-3 and RORgammat are important for determining the phenotype of allergic airway inflammation in a murine model of asthma. J Immunol, 2013, 190(3): 1056-1065.
22.	Chesne J, Braza F, Mahay G, et al. IL-17 in severe asthma. Where do we stand?. Am J Respir Crit Care Med, 2014, 190(10): 1094-1101.
23.	Zhao Y, Yang J, Gao YD, et al. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol, 2010, 151(4): 297-307.

1. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol, 2015, 16(1): 45-56.
2. Kujur W, Gurram RK, Haleem N, et al. Caerulomycin A inhibits Th2 cell activity: a possible role in the management of asthma. Sci Rep, 2015, 5: 15396.
3. 梁振宇, 蔡绍曦, 赵海金. 哮喘的临床与炎症表型. 中国呼吸与危重监护杂志, 2010, 9(5): 546-548.0.
4. Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol, 2013, 25(6): 755-760.
5. 李贱, 邹朋成, 杨莉容等. Th17 细胞在哮喘发病中的作用研究进展. 中国呼吸与危重监护杂志, 2013, 12(3): 322-324.0.
6. Kudo M, Melton AC, Chen C, et al. IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med, 2012, 18(4): 547-554.
7. Lajoie S, Lewkowich IP, Suzuki Y, et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol, 2010, 11(10): 928-935.
8. Bullens DM, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx?. Respir Res, 2006, 7: 135.
9. Finkelman FD, Hogan SP, Hershey GK, et al. Importance of cytokines in murine allergic airway disease and human asthma. J Immunol, 2010, 184(4): 1663-1674.
10. Ma C, Ma Z, Fu Q, et al. Curcumin attenuates allergic airway inflammation by regulation of CD4⁺CD25⁺ regulatory T cells (Tregs) /Th17 balance in ovalbumin-sensitized mice. Fitoterapia, 2013, 87: 57-64.
11. Park BS, Hong GU, Ro JY. Foxp3(+)-Treg cells enhanced by repeated low-dose gamma-irradiation attenuate ovalbumin-induced allergic asthma in mice. Radiat Res, 2013, 179(5): 570-583.
12. 周辰, 陈军浩, 殷凯生. 辅助性 T 细胞 17 和调节性 T 细胞在哮喘小鼠中的失衡表达及其意义. 中国呼吸与危重监护杂志, 2010, 9(1): 28-31.0.
13. Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med, 2014, 20(11): 1327-1333.
14. Yoshioka M, Sagara H, Takahashi F, et al. Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation. Am J Physiol Lung Cell Mol Physiol, 2009, 296(1): L30-L36.
15. Svensson RU, Parker SJ, Eichner LJ, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med, 2016, 22(10): 1108-1119.
16. Rodrigues HG, Takeo Sato F, Curi R, et al. Fatty acids as modulators of neutrophil recruitment, function and survival. Eur J Pharmacol, 2016, 785: 50-58.
17. Rehman A, Hemmert KC, Ochi A, et al. Role of fatty-acid synthesis in dendritic cell generation and function. J Immunol, 2013, 190(9): 4640-4649.
18. Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol, 2015, 36(2): 81-91.
19. Moon JS, Lee S, Park MA, et al. UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest, 2015, 125(2): 665-680.
20. Endo Y, Asou HK, Matsugae N, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep, 2015, 12(6): 1042-1055.
21. Ano S, Morishima Y, Ishii Y, et al. Transcription factors GATA-3 and RORgammat are important for determining the phenotype of allergic airway inflammation in a murine model of asthma. J Immunol, 2013, 190(3): 1056-1065.
22. Chesne J, Braza F, Mahay G, et al. IL-17 in severe asthma. Where do we stand?. Am J Respir Crit Care Med, 2014, 190(10): 1094-1101.
23. Zhao Y, Yang J, Gao YD, et al. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol, 2010, 151(4): 297-307.

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Acetyl CoA carboxylase promotes airway inflammation of asthma by inducing Th17 development

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