1. Academic Validation
  2. Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain

  • J Neuroinflammation. 2022 Jul 14;19(1):186. doi: 10.1186/s12974-022-02543-6.
Zhuang Peng  # 1 Sha Peng  # 1 Kangguang Lin  # 2 3 Bin Zhao  # 4 Lai Wei 4 Qinhui Tuo 1 Duanfang Liao 5 Tifei Yuan 6 7 8 Zhe Shi 9 10 11
Affiliations

Affiliations

  • 1 Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China.
  • 2 Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China.
  • 3 School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China.
  • 4 Xinxiang Key Laboratory of Forensic Toxicology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
  • 5 Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China. dfliao@hnucm.edu.cn.
  • 6 Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ytf0707@126.com.
  • 7 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. ytf0707@126.com.
  • 8 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China. ytf0707@126.com.
  • 9 Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China. zhezhe1106@163.com.
  • 10 Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. zhezhe1106@163.com.
  • 11 National Clinical Research Center for Mental Disorders, Changsha, Hunan, China. zhezhe1106@163.com.
  • # Contributed equally.
Abstract

Background: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect.

Methods: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated.

Results: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response.

Conclusions: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.

Keywords

Blood–brain barrier; Chronic restraint stress; Depressive-like behaviour; Neuroinflammation; T helper 17 cells.

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