ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation.

IF 6.2 2区医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2025-01-27 DOI:10.1186/s40478-025-01932-1

Yuan Chang, Yihua He, Di Wang, Kunxue Zhang, Yuzhen Zhang, Zhentong Li, Shuxin Zeng, Sheng Xiao, Suyue Pan, Kaibin Huang

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Abstract

Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production.

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来源期刊

Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine

CiteScore

11.20

自引率

2.80%

发文量

162

审稿时长

8 weeks

期刊介绍： "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.