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HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder

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作者：
Xu Ke[1,2] ; Wang Mingyang[3] ; Wang Haiyang[2,4] ; Zhao Shuang[5] ; Tu Dianji[6] ; Gong Xue[2] ; Li Wenxia[2] ; Liu Xiaolei[7] ; Zhong Lianmei[7,*1] ; Chen Jianjun[8,*2] ; Xie Peng[1,2,*3] ;
机构： [1]Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China [2]National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China [3]Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China [4]Key Laboratory of Psychoseomadsy, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China [5]Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, China [6]Department of Clinical Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China [7]Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China [8]Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
出处：
DOI： 10.1016/j.jare.2023.06.003
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摘要：
Neuroinflammation and autophagy are implicated in stress-related major depressive disorder (MDD), but the underlying molecular mechanisms remain largely unknown.Here, we identified that MDD regulated by HMGB1/STAT3/p65 axis mediated microglial activation and autophagy for the first time. Further investigations were performed to uncover the effects of this axis on MDD in vivo and in vitro.Bioinformatics analyses were used to re-analysis the transcriptome data from the dorsolateral prefrontal cortex (dlPFC) of post-mortem male MDD patients. The expression level of HMGB1 and its correlation with depression symptoms were explored in MDD clinical patients and chronic social defeat stress (CSDS)-induced depression model mice. Specific adeno-associated virus and recombinant (r)HMGB1 injection into the medial PFC (mPFC) of mice, and pharmacological inhibitors with rHMGB1 in two microglial cell lines exposed to lipopolysaccharide were used to analyze the effects of HMGB1/STAT3/p65 axis on MDD.The differential expression of genes from MDD patients implicated in microglial activation and autophagy regulated by HMGB1/STAT3/p65 axis. Serum HMGB1 level was elevated in MDD patients and positively correlated with symptom severity. CSDS not only induced depression-like states in mice, but also enhanced microglial reactivity, autophagy as well as activation of the HMGB1/STAT3/p65 axis in mPFC. The expression level of HMGB1 was mainly increased in the microglial cells of CSDS-susceptible mice, which also correlated with depressive-like behaviors. Specific HMGB1 knockdown produced a depression-resilient phenotype and suppressed the associated microglial activation and autophagy effects of CSDS-induced. The effects induced by CSDS were mimicked by exogenous administration of rHMGB1 or specific overexpression of HMGB1, while blocked by STAT3 inhibitor or p65 knockdown. In vitro, inhibition of HMGB1/STAT3/p65 axis prevented lipopolysaccharide-induced microglial activation and autophagy, while rHMGB1 reversed these changes.Our study established the role of microglial HMGB1/STAT3/p65 axis in mPFC in mediating microglial activation and autophagy in MDD.Copyright © 2023. Production and hosting by Elsevier B.V.

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大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
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Q1 MULTIDISCIPLINARY SCIENCES

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第一作者：
第一作者机构： [1]Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China [2]National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
通讯作者：
通讯机构： [1]Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China [2]National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China [7]Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China [8]Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China [*1]Department of Neurology, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China [*2]Institute of Life Sciences, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China [*3]National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
推荐引用方式(GB/T 7714)：
Xu Ke,Wang Mingyang,Wang Haiyang,et al.HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder[J].JOURNAL OF ADVANCED RESEARCH.2024,59:79-96.doi:10.1016/j.jare.2023.06.003.
APA：
Xu Ke,Wang Mingyang,Wang Haiyang,Zhao Shuang,Tu Dianji...&Xie Peng.(2024).HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder.JOURNAL OF ADVANCED RESEARCH,59,
MLA：
Xu Ke,et al."HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder".JOURNAL OF ADVANCED RESEARCH 59.(2024):79-96

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