DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke

Author:

Lyu Tian‐Jie12ORCID,Qiu Xin12,Wang Yubo12,Zhang Ling1,Dai Yalun12,Wang Xuechun12,Zhao Shunying2,Xiang Meilin2,Cui Lu2,Cheng Si12,Liu Yang2,Gu Hongqiu2,Jiang Yong2,Meng Xia12,Wang Yilong1,Zhao Xingquan1,Wang Xianwei3,Li Qian4,Wang Meng2,Jiang Yingyu2,Xu Zhe2,Huang Xinying2,Li Hao2,Wang Yongjun12567,Li Zixiao12568

Affiliation:

1. Department of Neurology Beijing Tiantan Hospital Capital Medical University Beijing China

2. China National Clinical Research Center for Neurological Diseases Beijing China

3. Center for Metabolic Disease Research Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA

4. Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Capital Medical University Beijing China

5. Clinical Center for Precision Medicine in Stroke Capital Medical University Beijing China

6. Advanced Innovation Center for Human Brain Protection Capital Medical University Beijing China

7. Research Unit of Artificial Intelligence in Cerebrovascular Disease Chinese Academy of Medical Sciences Beijing China

8. Beijing Engineering Research Center of Digital Healthcare for Neurological Diseases Beijing China

Abstract

AbstractSomatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well‐characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A‐driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Beijing Municipality

Ministry of Science and Technology of the People's Republic of China

Publisher

Wiley

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