BACKGROUND Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. METHODS To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively. RESULTS Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition. CONCLUSIONS These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.

中文翻译：

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TREM-2-p38 MAPK信号传导调节慢性脑灌注不足并伴有糖尿病的神经炎症。

背景技术糖尿病（DM）和慢性脑灌注不足（CCH）都是认知障碍的危险因素。然而，DM和CCH是否可以协同促进认知障碍，相关的病理机制仍不清楚。方法为研究DM和CCH对认知功能的影响，以高脂饮食（HFD），小剂量链脲佐菌素（STZ），双侧颈总动脉闭塞（BCCAO）的方式诱导大鼠模拟DM和CCH。体内和小鼠BV2小胶质细胞暴露于低氧和/或高葡萄糖下，以模拟CCH并在体外与DM病变并存。为了进一步探讨其潜在机制，分别使用TREM-2特异性小干扰RNA和TREM-2过表达慢病毒来敲除和过表达TREM-2。结果认知缺陷 当DM在体内和体外叠加在CCH上时，神经元细胞死亡，具有小胶质细胞活化的神经炎症和TREM-2-MAPK信号传导均得到增强。操纵TREM-2表达水平可显着调节p38 MAPK信号转导和体外炎症反应。在高葡萄糖和低氧条件下，TREM-2敲除增强，而TREM-2过表达抑制p38 MAPK信号传导和随后的促炎性介质产生。结论这些结果表明，当DM协同叠加在CCH上时，TREM-2负调控p38 MAPK介导的炎症反应，并突出了TREM-2作为DM和CCH潜在免疫调节靶标的重要性。当在体内和体外将DM叠加在CCH上时，MMP3和TREM-2-MAPK信号转导都得到增强。操纵TREM-2表达水平可显着调节p38 MAPK信号转导和体外炎症反应。在高葡萄糖和低氧条件下，TREM-2敲除增强，而TREM-2过表达抑制p38 MAPK信号传导和随后的促炎性介质产生。结论这些结果表明，当DM协同叠加在CCH上时，TREM-2负调控p38 MAPK介导的炎症反应，并突出了TREM-2作为DM和CCH潜在免疫调节靶标的重要性。当在体内和体外将DM叠加在CCH上时，MMP3和TREM-2-MAPK信号转导都增强。操纵TREM-2表达水平可显着调节p38 MAPK信号转导和体外炎症反应。在高葡萄糖和低氧条件下，TREM-2敲除增强，而TREM-2过表达抑制p38 MAPK信号传导和随后的促炎性介质产生。结论这些结果表明，当DM协同叠加在CCH上时，TREM-2负调控p38 MAPK介导的炎症反应，并突出了TREM-2作为DM和CCH潜在免疫调节靶标的重要性。在高葡萄糖和低氧条件下，TREM-2敲除增强，而TREM-2过表达抑制p38 MAPK信号传导和随后的促炎性介质产生。结论这些结果表明，当DM协同叠加在CCH上时，TREM-2负调控p38 MAPK介导的炎症反应，并突出了TREM-2作为DM和CCH潜在免疫调节靶标的重要性。在高葡萄糖和低氧条件下，TREM-2敲除增强，而TREM-2过表达抑制p38 MAPK信号传导和随后的促炎性介质产生。结论这些结果表明，当DM协同叠加在CCH上时，TREM-2负调控p38 MAPK介导的炎症反应，并突出了TREM-2作为DM和CCH潜在免疫调节靶标的重要性。