FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury
Abstract 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 remai...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-03-01
|
| Series: | Military Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40779-024-00523-w |
| _version_ | 1797233757819764736 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Mi Zhou |
| collection | DOAJ |
| description | Abstract 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 in vitro and in vivo 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 represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI. |
| first_indexed | 2024-04-24T16:21:15Z |
| format | Article |
| id | doaj.art-7ebf1a81a9d44766a652c01fdffff14a |
| institution | Directory Open Access Journal |
| issn | 2054-9369 |
| language | English |
| last_indexed | 2024-04-24T16:21:15Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj.art-7ebf1a81a9d44766a652c01fdffff14a2024-03-31T11:13:30ZengBMCMilitary Medical Research2054-93692024-03-0111112110.1186/s40779-024-00523-wFOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injuryMi Zhou0Yang-Wu-Yue Liu1Yu-Hang He2Jing-Yu Zhang3Hao Guo4Hao Wang5Jia-Kui Ren6Yi-Xun Su7Teng Yang8Jia-Bo Li9Wen-Hui He10Peng-Jiao Ma11Man-Tian Mi12Shuang-Shuang Dai13Department of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityResearch Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Institute of Military Preventive Medicine, Army Medical UniversityDepartment of Neurosurgery, Daping Hospital, Army Medical UniversityDepartment of Trauma and Emergency, Southwest Hospital, Army Medical UniversityDepartment of Neurosurgery, Daping Hospital, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityDepartment of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Brain and Intelligence Research Key Suyixun Laboratory of Chongqing Education Commission, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityResearch Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Institute of Military Preventive Medicine, Army Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medicine, Army Medical UniversityAbstract 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 in vitro and in vivo 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 represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.https://doi.org/10.1186/s40779-024-00523-wTraumatic brain injury (TBI)NeutrophilForkhead box protein O1 (FOXO1)Acute stageChronic stage |
| spellingShingle | 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 FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury Military Medical Research Traumatic brain injury (TBI) Neutrophil Forkhead box protein O1 (FOXO1) Acute stage Chronic stage |
| title | FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| title_full | FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| title_fullStr | FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| title_full_unstemmed | FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| title_short | FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| title_sort | foxo1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury |
| topic | Traumatic brain injury (TBI) Neutrophil Forkhead box protein O1 (FOXO1) Acute stage Chronic stage |
| url | https://doi.org/10.1186/s40779-024-00523-w |
| work_keys_str_mv | AT mizhou foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT yangwuyueliu foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT yuhanghe foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT jingyuzhang foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT haoguo foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT haowang foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT jiakuiren foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT yixunsu foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT tengyang foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT jiaboli foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT wenhuihe foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT pengjiaoma foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT mantianmi foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury AT shuangshuangdai foxo1reshapesneutrophilstoaggravateacutebraindamageandpromotelatedepressionaftertraumaticbraininjury |