Early-life undernutrition reprograms CD4+ T-cell glycolysis and epigenetics to facilitate asthma - 06/06/19
Abstract |
Background |
Exposure to early-life undernutrition is closely related to higher risks of adverse immunologic outcomes in adulthood. Although it has been suggested that asthma has its origins in early life, its underlying mechanisms remain largely unknown.
Objective |
We characterized the effects of early-life undernutrition on T lymphocytes, which play a pivotal role in immune diseases, and we investigated whether this contributes to susceptibility to asthma in adulthood.
Methods |
Pregnant mice were fed a protein restriction diet (PRD) to establish an early-life undernutrition model. Naive CD4+ T cells (CD4+CD62LhiCD44−) from offspring were used throughout the study. TH2 differentiation was examined by using fluorescence-activated cell sorting and ELISA under TH2-polarized conditions in vitro and through ovalbumin-induced experimental asthma in vivo. T-cell metabolism was measured with a Seahorse XF96 Analyzer. DNA methylation levels were measured by using bisulfite sequencing.
Results |
PRD CD4+ T cells displayed increased activation and proliferation and were prone to differentiate into TH2 cells both in vitro and in vivo, leading to susceptibility to experimental asthma. Mechanistically, early-life undernutrition upregulated mechanistic target of rapamycin 1–dependent glycolysis and induced conserved noncoding DNA sequence 1 DNA hypomethylation in the TH2 cytokine locus of CD4+ T cells. Glycolysis blockades undermined increased TH2 skewing and alleviated experimental asthma in PRD mice.
Conclusion |
Early-life undernutrition induced mechanistic target of rapamycin 1–dependent glycolysis upregulation and TH2 cytokine locus hypomethylation in CD4+ T cells, resulting in increased T-cell activation, proliferation, and TH2 skewing and further susceptibility to experimental asthma.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Early-life undernutrition, asthma, CD4+ T cells, glycolysis, DNA methylation
Abbreviations used : 7-AAD, Arg1, BALF, CNS1, 2-DG, ECAR, FCCP, Fizz1, Hk2, IUGR, Ldha, mTORC, NCD, OCR, OVA, Pkm, PRD, Tpi, Treg, Ym1
Plan
This study was supported by the National Key Research and Development Program of China (2017YFC1001303 to H.H.), the National Natural Science Foundation of China (31471405 to H.H. and 81671456 to X.L.), the major program of the National Natural Science Foundation of China (81490742 to H.H.), the Shanghai Sailing Program (17YF1420700 to X.C.), the China Postdoctoral Science Foundation (2016M601616 to X.C.), the International Cooperation Project of China and Canada NSFC (81661128010 to H.H.), the Interdisciplinary Key Program of Shanghai Jiao Tong University (YG2014ZD08 to H.H.), and the Shen Kang Three Year Action plan (16CR3003A to H.H.). |
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2038 - juin 2019 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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