S100a9 Protects Against the Effects of Repeated Social Defeat Stress.
S100a9 Protects Against the Effects of Repeated Social Defeat Stress.
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S100A9可以防止反复的社会失败压力的影响。
DOI：
10.1016/j.bpsgos.2022.12.002
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发表时间：
2023-10
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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创伤后应激障碍是心理创伤的后果，与炎症增加和患共病炎症性疾病的风险增加有关。然而，这种心理健康障碍和炎症之间的机械联系仍然难以捉摸。我们先前发现，S100a8和S100a9信使RNA，编码蛋白钙卫蛋白的基因，在T淋巴细胞中显著上调，并与这些细胞中的炎症基因表达和线粒体氧化还原环境呈正相关。因此，我们假设钙卫蛋白的基因缺失会减弱心理创伤后表现出的炎症和氧化还原表型。我们使用了创伤后应激障碍的临床前小鼠模型，称为反复社交失败应激（RSDS），结合S100a9（功能性消除钙卫蛋白）的药理学和遗传学操作。这些研究共使用了186只动物（93只对照组，93只RSDS组）。出乎意料的是，我们观察到与野生型动物相比，RSDS后小鼠的行为病理学、炎症和线粒体氧化还原环境恶化。此外，钙卫蛋白的损失显着增加了T淋巴细胞的代谢需求，这表明这种蛋白质可能在线粒体调节中发挥了未描述的作用。单细胞RNA测序分析进一步支持了这一点，表明RSDS和S100a9的缺失主要改变了与线粒体功能和氧化磷酸化相关的基因。这些数据表明，钙卫蛋白的损失增强了SDS诱导的表型，这表明其在心理创伤后观察到的上调可能提供以前未探索的保护功能。
Posttraumatic stress disorder, a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. We previously found that S100a8 and S100a9 messenger RNA, genes that encode the protein calprotectin, were significantly upregulated in T lymphocytes and positively correlated with inflammatory gene expression and the mitochondrial redox environment in these cells. Therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after psychological trauma. We used a preclinical mouse model of posttraumatic stress disorder known as repeated social defeat stress (RSDS) combined with pharmacological and genetic manipulation of S100a9 (which functionally eliminates calprotectin). A total of 186 animals (93 control, 93 RSDS) were used in these studies. Unexpectedly, we observed worsening of behavioral pathology, inflammation, and the mitochondrial redox environment in mice after RSDS compared with wild-type animals. Furthermore, loss of calprotectin significantly enhanced the metabolic demand on T lymphocytes, suggesting that this protein may play an undescribed role in mitochondrial regulation. This was further supported by single-cell RNA sequencing analysis demonstrating that RSDS and loss of S100a9 primarily altered genes associated with mitochondrial function and oxidative phosphorylation. These data demonstrate that the loss of calprotectin potentiates the RSDS-induced phenotype, which suggests that its observed upregulation after psychological trauma may provide previously unexplored protective functions.
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影响因子：
30.5
作者：
Alves de Lima K;Rustenhoven J;Da Mesquita S;Wall M;Salvador AF;Smirnov I;Martelossi Cebinelli G;Mamuladze T;Baker W;Papadopoulos Z;Lopes MB;Cao WS;Xie XS;Herz J;Kipnis J
通讯作者：
Kipnis J
影响因子：
7.3
作者：
Foell, D.;Wittkowski, H.;Clancy, R.
通讯作者：
Clancy, R.
影响因子：
3.4
作者：
Foster, Russell;Kandanearatchi, Apsara;Everall, Ian P.
通讯作者：
Everall, Ian P.
影响因子：
2.7
作者：
Bratton, B. O.;Martelli, D.;McAllen, R. M.
通讯作者：
McAllen, R. M.
影响因子：
3.2
作者：
Broome, AM;Ryan, D;Eckert, RL
通讯作者：
Eckert, RL