FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury  

作　　者：Mi Zhou Yang-Wu-Yue Liu Yu-Hang He Jing-Yu Zhang Hao Guo Hao Wang Jia-Kui Ren Yi-Xun Su Teng Yang Jia-Bo Li Wen-Hui He Peng-Jiao Ma Man-Tian Mi Shuang-Shuang Dai 

机构地区：[1]Department of Biochemistry and Molecular Biology,School of Basic Medicine,Army Medical University,Chongqing 400038,China [2]Research Center for Nutrition and Food Safety,Chongqing Key Laboratory of Nutrition and Health,Institute of Military Preventive Medicine,Army Medical University,Chongqing 400038,China [3]Department of Neurosurgery,Daping Hospital,Army Medical University,Chongqing 400042,China [4]Department of Trauma and Emergency,Southwest Hospital,Army Medical University,Chongqing 400038,China [5]Department of Histology and Embryology,Chongqing Key Laboratory of Neurobiology,Brain and Intelligence Research Key Suyixun Laboratory of Chongqing Education Commission,Army Medical University,Chongqing 400038,China [6]Research Center,Seventh Affiliated Hospital of Sun Yat-Sen University,Shenzhen 518107,Guangdong,China

出　　处：《Military Medical Research》2024年第4期521-542,共22页军事医学研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(82071779 and 81901626);the Science Fund for Creative Research Groups of Chongqing Municipal Education Commission of China,the grants from the Talent Foundation of Army Medical University(to Shuang-Shuang Dai);the Scientific Research Grant(ALJ22J003);the Chongqing Natural Science Foundation of China(CSTB2022NSCQ-MSX0177).

摘　　要：Background:Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury(TBI).However,the heterogeneity,multifunctionality,and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood.Methods:Using the combined single-cell transcriptomics,metabolomics,and proteomics analysis from TBI patients and the TBI mouse model,we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests.We also characterized the underlying mechanisms both invitro and invivo through molecular simulations,signaling detections,gene expression regulation assessments[including dual-luciferase reporter and chromatin immunoprecipitation(ChIP)assays],primary cultures or co-cultures of neutrophils and oligodendrocytes,intracellular iron,and lipid hydroperoxide concentration measurements,as well as forkhead box protein O1(FOXO1)conditional knockout mice.Results:We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model.Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI,aggravating acute brain inflammatory damage and promoting late TBI-induced depression.In the acute stage,FOXO1 upregulated cytoplasmic Versican(VCAN)to interact with the apoptosis regulator B-cell lymphoma-2(BCL-2)-associated X protein(BAX),suppressing the mitochondrial translocation of BAX,which mediated the antiapoptotic effect companied with enhancing interleukin-6(IL-6)production of FOXO1high neutrophils.In the chronic stage,the“FOXO1-transferrin receptor(TFRC)”mechanism contributes to FOXO1high neutrophil ferroptosis,disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein,which contributes to the progression of late depression after TBI.Conclusions:FOXO1high neutrophils repr

关 键 词：Traumatic brain injury(TBI) NEUTROPHIL Forkhead box protein O1(FOXO1) Acute stage Chronic stage 

分 类 号：R651.15[医药卫生—外科学]