Activation of sigma non-opioid intracellular receptor 1 (S1R) receptor inhibits plexin domain containing 2 (Plxdc2) driven microglial inflammation to ameliorate depressive-like behaviours in mice

IF 7.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2026-09-02 Epub Date: 2026-07-15 DOI:10.1111/bph.70598

Jing-Ya Wang, Peng Ren, De-Yi Yang, Han Ni, Shuang Zhang, Chen- Xing Yue, Zhi-Rui Zeng, Zeng-Qiang Yuan, Yun-Feng Li

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Abstract

Background and Purpose

Microglia are central regulators of neuroinflammation in depression. Drivers involved remain incompletely understood. Sigma non-opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.

Experimental Approach

Using integrated machine learning and single-cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-stimulated BV-2 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.

Key Results

Plxdc2 was the key gene up-regulated at both transcriptional and protein levels in blood and depression-susceptible brain regions. Single-cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N-linked glycosylation (NLG). LPS-treated mice, depressive-like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation-related enzyme β-1,4-galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL-0919) or conditional knockdown of Plxdc2, reversed these molecular changes, reduced neuroinflammation and alleviated depressive-like behaviours. Analysis demonstrated that overexpressing Plxdc2 in mPFC microglia activated the JAK2-STAT1 pathway, enhanced NLG, shifting microglia towards a pro-inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive-like behaviour. These were reversible by the NLG inhibitor tunicamycin.

Conclusions and Implications

Plxdc2 promotes depressive-like behaviours by dysregulating NLG-mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R-Plxdc2 axis as a potential target for modulating microglial function in inflammation-related depression.

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激活sigma非阿片样细胞内受体1 （S1R）受体抑制丛蛋白结构域2 （Plxdc2）驱动的小胶质细胞炎症以改善小鼠抑郁样行为。

背景与目的：小胶质细胞是抑郁症患者神经炎症的中枢调节因子。有关司机的情况仍不完全清楚。Sigma非阿片样细胞内受体1 （S1R）参与脑炎症。本研究探讨了S1R如何调节与抑郁症相关的神经炎症。实验方法：利用综合机器学习和单细胞转录组学，确定了抑郁症中涉及小胶质细胞功能障碍的关键基因。在脂多糖（LPS）诱导的小鼠抑郁模型和LPS刺激的BV-2细胞中检测了其相关性。此外，在内侧前额叶皮层（mPFC）小胶质细胞上进行靶向敲低或过表达该基因，然后进行综合行为，细胞和分子分析。关键结果：Plxdc2是血液和抑郁易感脑区转录和蛋白水平上调的关键基因。单细胞RNA测序证实了其在小胶质细胞中的特异性富集，特别是在与n -链糖基化（NLG）相关的炎症基因组中。lps处理小鼠，抑郁样行为伴随着mPFC小胶质细胞Plxdc2和糖基化相关酶β-1,4-半乳糖基转移酶1的表达升高。S1R激动剂盐酸Hypidone （YL-0919）或Plxdc2的条件下调可逆转这些分子变化，减少神经炎症并缓解抑郁样行为。分析表明，在mPFC小胶质细胞中过表达Plxdc2激活了JAK2-STAT1通路，增强了NLG，将小胶质细胞转向促炎表型，加剧了突触可塑性的缺陷，并诱导了抑郁样行为。这些是可逆的NLG抑制剂tunicamycin。结论和意义：Plxdc2通过失调nlg介导的小胶质细胞炎症促进抑郁样行为。S1R激活通过抑制该通路具有治疗作用，将S1R- plxdc2轴定位为炎症相关抑郁症中调节小胶质细胞功能的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.