Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction

Jialin Ye, Jiemeng Fu, Hui Hou, Yan Wang, Wei Deng, Shumeng Hao, Yifei Pei, Jing Xu, Mingyue Zheng, Yichuan Xiao

Life Medicine ›› 2023, Vol. 2 ›› Issue (3) : 7.

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Life Medicine ›› 2023, Vol. 2 ›› Issue (3) : 7. DOI: 10.1093/lifemedi/lnad021
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Article

Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction

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Abstract

DNA accumulation is associated with the development of autoimmune inflammatory diseases. However, the pathological role and underlying mechanism of cytoplasmic DNA accumulation in CD4+ T cells have not been well established. Here, we show that Trex1 deficiency-induced endogenous DNA accumulation in CD4+ T cells greatly promoted their induction of autoimmune inflammation in a lupus-like mouse model. Mechanistically, the accumulated DNA in CD4+ T cells was sensed by the KU complex, then triggered the activation of DNA-PKcs and ZAK and further facilitated the activation of AKT, which exacerbated glycolysis, thereby promoting the inflammatory responses. Accordingly, blocking the DNA sensing pathway in CD4+ T cells by genetic knockout of Zak or using our newly developed ZAK inhibitor iZAK2 attenuated all pathogenic characteristics in a lupus-like inflammation mouse model induced with Trex1-deficient CD4+ T cells. Overall, our study demonstrated a causal link between DNA-sensing and metabolic reprogramming in CD4+ T cells for inflammatory induction and suggested inhibition of the DNA sensing pathway may be a potential therapy for the treatment of inflammatory diseases.

Keywords

CD4+ T / DNA sensing / glycolysis / inflammation / autoimmunity disease

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Jialin Ye, Jiemeng Fu, Hui Hou, Yan Wang, Wei Deng, Shumeng Hao, Yifei Pei, Jing Xu, Mingyue Zheng, Yichuan Xiao. Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction. Life Medicine, 2023, 2(3): 7 https://doi.org/10.1093/lifemedi/lnad021

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2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.
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