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

作者全名：Xu, Ke; Wang, Mingyang; Wang, Haiyang; Zhao, Shuang; Tu, Dianji; Gong, Xue; Li, Wenxia; Liu, Xiaolei; Zhong, Lianmei; Chen, Jianjun; Xie, Peng

作者地址：[Xu, Ke; Xie, Peng] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing, Peoples R China; [Xu, Ke; Wang, Haiyang; Gong, Xue; Li, Wenxia; Xie, Peng] Chongqing Med Univ, Affiliated Hosp 1, Natl Hlth Commiss Key Lab Diag & Treatment Brain F, Chongqing 400016, Peoples R China; [Wang, Mingyang] Chinese Acad Sci, Kunming Inst Zool, Kunming 650223, Peoples R China; [Wang, Haiyang] Chongqing Med Univ, Stomatol Hosp, Key Lab Psychoseomadsy, Chongqing 401147, Peoples R China; [Zhao, Shuang] Chongqing Med Univ, Dept Pathophysiol, Chongqing 400016, Peoples R China; [Tu, Dianji] Third Mil Med Univ, Xinqiao Hosp, Dept Clin Lab, Chongqing 400037, Peoples R China; [Liu, Xiaolei; Zhong, Lianmei] Kunming Med Univ, Affiliated Hosp 1, Dept Neurol, 295 Xicha Rd, Kunming 650032, Peoples R China; [Chen, Jianjun] Chongqing Med Univ, Inst Life Sci, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China; [Xie, Peng] Chongqing Med Univ, Affiliated Hosp 1, Natl Hlth Commiss Key Lab Diag & Treatment Brain F, Yixueyuan Rd, Chongqing, Peoples R China

通信作者：Zhong, LM (通讯作者)，Kunming Med Univ, Affiliated Hosp 1, Dept Neurol, 295 Xicha Rd, Kunming 650032, Peoples R China.; Chen, JJ (通讯作者)，Chongqing Med Univ, Inst Life Sci, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China.; Xie, P (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Natl Hlth Commiss Key Lab Diag & Treatment Brain F, Yixueyuan Rd, Chongqing, Peoples R China.

来源：JOURNAL OF ADVANCED RESEARCH

ESI学科分类：Multidisciplinary

WOS号：WOS:001236836500001

JCR分区：Q1

影响因子：11.4

年份：2024

卷号：59

期号：　

开始页：79

结束页：96

文献类型：Article

关键词：Major depressive disorder; Medial prefrontal cortex; Microglial; HMGB1/STAT3/p65 axis; Neuroinflammation; Autophagy

摘要：Introduction: Neuroinflammation and autophagy are implicated in stress -related major depressive disorder (MDD), but the underlying molecular mechanisms remain largely unknown. Objectives: 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 . Methods: 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. Results: 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. Conclusion: Our study established the role of microglial HMGB1/STAT3/p65 axis in mPFC in mediating microglial activation and autophagy in MDD. 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

基金机构：　

基金资助正文：