HMGB1/STAT3/p65 轴驱动小胶质细胞活化，自噬在慢性应激诱导的重度抑郁症中发挥关键作用。
HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder.
机构信息
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
出版信息
J Adv Res. 2024 May;59:79-96. doi: 10.1016/j.jare.2023.06.003. Epub 2023 Jun 13.
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.
简介
神经炎症和自噬与应激相关的重度抑郁症（MDD）有关，但其中的潜在分子机制在很大程度上尚不清楚。
目的
本研究首次发现，HMGB1/STAT3/p65 轴调控的 MDD 会首先导致小胶质细胞激活和自噬。进一步的研究旨在揭示该轴在线粒体和体外对 MDD 的影响。
方法
使用生物信息学分析方法重新分析了尸检男性 MDD 患者背外侧前额叶皮层（dlPFC）的转录组数据。在 MDD 临床患者和慢性社会挫败应激（CSDS）诱导的抑郁模型小鼠中探索了 HMGB1 的表达水平及其与抑郁症状的相关性。通过腺相关病毒和重组（r）HMGB1 注射到小鼠的内侧前额叶皮质（mPFC），以及在两种小胶质细胞系中用 rHMGB1 处理时使用药理学抑制剂，分析了 HMGB1/STAT3/p65 轴对 MDD 的影响。
结果
MDD 患者的基因差异表达与 HMGB1/STAT3/p65 轴调控的小胶质细胞激活和自噬有关。MDD 患者的血清 HMGB1 水平升高，且与症状严重程度呈正相关。CSDS 不仅在小鼠中诱导出抑郁样状态，而且还增强了 mPFC 中的小胶质细胞反应性、自噬以及 HMGB1/STAT3/p65 轴的激活。HMGB1 的表达水平主要在 CSDS 易感小鼠的小胶质细胞中增加，且与抑郁样行为相关。特异性 HMGB1 敲低产生了抗抑郁表型，并抑制了 CSDS 诱导的相关小胶质细胞激活和自噬作用。CSDS 诱导的作用可被外源性 rHMGB1 或 HMGB1 的特异性过表达模拟，而被 STAT3 抑制剂或 p65 敲低阻断。在体外，抑制 HMGB1/STAT3/p65 轴可防止脂多糖诱导的小胶质细胞激活和自噬，而 rHMGB1 则逆转了这些变化。
结论
本研究确立了 mPFC 中小胶质细胞 HMGB1/STAT3/p65 轴在介导 MDD 中小胶质细胞激活和自噬中的作用。
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