Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China; Clinical Neuroscience Institute, Jinan University, Guangzhou, Guangdong, China.
Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China; Clinical Neuroscience Institute, Jinan University, Guangzhou, Guangdong, China.
Biochem Biophys Res Commun. 2020 Aug 27;529(3):554-561. doi: 10.1016/j.bbrc.2020.05.056. Epub 2020 Jul 15.
Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.
中风是全球范围内导致残疾和死亡的第二大原因。髓样细胞表达的触发受体（TREM）-1 负责激活先天免疫反应，并且在炎症中起关键作用。在这项研究中，我们报道了 TREM-1 在大鼠大脑中动脉闭塞（MCAO）模型缺血损伤后的作用。该研究还表明，TREM-1 在大鼠脑梗死时表达上调。通过其选择性抑制剂 LP17 来确定 TREM-1 的抑制作用，表明其对脑梗死损伤具有神经保护作用。研究结果表明，通过给予 LP17 抑制 TREM-1 可改善脑损伤，减少缺血面积和脑含水量。此外，LP17 降低 MCAO 诱导的小胶质细胞激活和神经变性，表现为小胶质细胞 Iba-1 和 FJ-B 阳性细胞表达减少，神经元丢失逆转。此外，LP17 对缺血性神经元损伤的作用可能与促炎细胞因子产生减少和抗炎细胞因子 IL-10 产生增加有关。体内和体外研究均表明，抑制 TREM-1 可减少 ROS 积聚、脂质过氧化（LPO）含量（如丙二醛（MDA）），并增强超氧化物歧化酶（SOD）活性。抑制 TREM-1 可减轻 MCAO 大鼠的炎症和细胞焦亡。这是通过抑制 NLRP3、半胱天冬酶-1、ASC（一种含 CARD 的凋亡相关斑点样蛋白）和 Gasdermin D 的水平来实现的。这些结果证实，抑制 TREM-1 通过减少氧化应激和细胞焦亡来保护缺血诱导的神经元损伤并减轻小胶质细胞介导的神经炎症。因此，阻断 TREM-1 表达为改善缺血性中风提供了一种有效的干预措施。
