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

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

doi:10.1186/s40779-024-00523-w

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

RESEARCH | Updated：2025-12-13

- FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury
- Military Medical Research Vol. 11, Issue 4, Pages: 521-542(2024)
- Affiliations：
  
  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
- Author bio：
  
  Mi Zhou, Yang-Wu-Yue Liu and Yu-Hang He contributed equally to this work
  *mantian_mi@tmmu.edu.cn;
  daiyuyang268@aliyun.com
- Funds：
- DOI：10.1186/s40779-024-00523-w
  CLC：
- Published：2024-08
- Accepted：
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Cite this article as: Zhou M, Liu YWY, He YH, Zhang JY, Guo H, Wang H, et al. FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury. Mil Med Res. 2024;11(1):20.
DOI：

Cite this article as: Zhou M, Liu YWY, He YH, Zhang JY, Guo H, Wang H, et al. FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury. Mil Med Res. 2024;11(1):20. DOI： 10.1186/s40779-024-00523-w.

摘要

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 FOXO1

high

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 FOXO1

high

neutrophils. In the chronic stage

the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1

high

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:

FOXO1

high

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 neut

rophils in TBI.

关键词

Keywords

references

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