Functions of resolvin D1-ALX/FPR2 receptor interaction in the hemoglobin-induced microglial inflammatory response and neuronal injury
Functions of resolvin D1-ALX/FPR2 receptor interaction in the hemoglobin-induced microglial inflammatory response and neuronal injury
复制标题
Resolvin D1-ALX/FPR2 受体相互作用在血红蛋白诱导的小胶质细胞炎症反应和神经元损伤中的功能。
DOI：
10.1186/s12974-020-01918-x
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发表时间：
2020-08-14
影响因子：
9.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Liu, Guang-Jie;Tao, Tao;Li, Wei
研究背景早期脑损伤(EBI)被认为是影响蛛网膜下腔出血(SAH)预后的关键因素。EBI涉及多种病理过程，炎症和神经元死亡在这一过程中起关键作用。RvD1通过与脂氧素A4受体/甲酰肽受体2(ALX/FPR2)相互作用，在多种疾病中显示出优异的抗炎作用。然而，它在中枢神经系统(CNS)中的作用仍然没有得到很好的描述。因此，本研究的目的是阐明SAH后RvD1-ALX/FPR2相互作用在脑内的潜在作用。在我们的实验中，Rvd1的浓度为25 nM。采用Western blotting、定量聚合酶链式反应(QPCR)、免疫荧光等方法检测ALX/FPR2表达的细胞定位和时程变化，评价RvD1对Hb诱导的原代小胶质细胞活化和神经元损伤的影响，证实ALX/FPR2在RvD1功能中的作用。Rvd1对Hb诱导的小胶质细胞炎症反应具有良好的抑制作用，其机制可能与调节IRAK1/TRAF6/NF-κB或MAPK信号通路有关。Rvd1还有可能减轻Hb诱导的神经元氧化损伤和细胞凋亡。ALX/FPR2特异性拮抗剂Trp-Arg-Trp-NH2(WRW4)可逆转小胶质细胞IRAK1/TRAF6和神经元GPX1/bclxL的mRNA表达，提示ALX/FPR2可介导RvD1的神经保护作用。结论RvD1-ALX/FPR2的相互作用可能在中枢神经系统起双重作用，抑制Hb促进小胶质细胞促炎极化，减轻Hb诱导的神经元氧化损伤和死亡。这些结果为治疗SAH和其他与炎症相关的脑部疾病提供了良好的治疗靶点(ALX/FPR2)和潜在的有效药物(RvD1)。
BackgroundEarly brain injury (EBI) has been thought to be a key factor affecting the prognosis of subarachnoid hemorrhage (SAH). Many pathologies are involved in EBI, with inflammation and neuronal death being crucial to this process. Resolvin D1 (RvD1) has shown superior anti-inflammatory properties by interacting with lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in various diseases. However, it remains not well described about its role in the central nervous system (CNS). Thus, the goal of the present study was to elucidate the potential functions of the RvD1-ALX/FPR2 interaction in the brain after SAH.MethodsWe used an in vivo model of endovascular perforation and an in vitro model of hemoglobin (Hb) exposure as SAH models in the current study. RvD1 was used at a concentration of 25 nM in our experiments. Western blotting, quantitative polymerase chain reaction (qPCR), immunofluorescence, and other chemical-based assays were performed to assess the cellular localizations and time course fluctuations in ALX/FPR2 expression, evaluate the effects of RvD1 on Hb-induced primary microglial activation and neuronal damage, and confirm the role of ALX/FPR2 in the function of RvD1.ResultsALX/FPR2 was expressed on both microglia and neurons, but not astrocytes. RvD1 exerted a good inhibitory effect in the microglial pro-inflammatory response induced by Hb, possibly by regulating the IRAK1/TRAF6/NF-κB or MAPK signaling pathways. RvD1 could also potentially attenuate Hb-induced neuronal oxidative damage and apoptosis. Finally, the mRNA expression of IRAK1/TRAF6 in microglia and GPx1/bcl-xL in neurons was reversed by the ALX/FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4), indicating that ALX/FPR2 could mediate the neuroprotective effects of RvD1.ConclusionsThe results of the present study indicated that the RvD1-ALX/FPR2 interaction could potentially play dual roles in the CNS, as inhibiting Hb promoted microglial pro-inflammatory polarization and ameliorating Hb induced neuronal oxidant damage and death. These results shed light on a good therapeutic target (ALX/FPR2) and a potential effective drug (RvD1) for the treatment of SAH and other inflammation-associated brain diseases.