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Candesartan modulates microglia activation and polarization via NF-κB signaling pathway
International Journal of Immunopathology and Pharmacology ( IF 3.5 ) Pub Date : 2020-11-25 , DOI: 10.1177/2058738420974900
Shuyan Qie 1 , Yuanyuan Ran 2 , Xiaosheng Lu 3 , Wei Su 4 , Wei Li 1 , Jianing Xi 5 , Weijun Gong 5 , Zongjian Liu 2
Affiliation  

Microglia are diverse cells that acquire different functional phenotypes in response to microenvironment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. They are mainly stimulated into two opposing phenotypes, classically (M1) and alternatively (M2) phenotype. Regulating microglia polarization from M1 to M2 state has been suggested as a potential therapeutic approach in treatment of CNS disorders. Candesartan, an angiotensin II type I receptors antagonist, exerts beneficial effects for antioxidant, anti-inflammation, neurotrophic, and anti-apoptotic function. However, the effect of candesartan on microglia polarization and underlying mechanisms remain unknown. In this study, the resting microglia were stimulated to M1 microglia with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and then treated with vehicle or candesartan for 24 h. RT-PCR was utilized to detect the mRNA expression of microglia phenotype markers and inflammatory cytokines. Microglia phenotype markers and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway were determined by western blot. A neuron-microglia co-culture system was used to determine whether candesartan could ameliorate the neurotoxic effect of M1 microglia to oxygen-glucose deprivation (OGD) neuron. Candesartan treatment reduced the expression of M1 markers, and increased M2 markers. Meanwhile, candesartan reduced fluorescence intensity and protein level of M1 marker and enhanced M2 marker. Candesartan also regulated the neuroinflammatory response via reducing the release of pro-inflammatory cytokines and increasing anti-inflammatory cytokines in LPS + IFN-γ stimulated BV2 cells. Candesartan markedly inhibited the protein level of TLR4, the phosphorylation of IKBα and p65, and suppressed nuclear translocation of NF-κB p65. BAY 11-7085, a NF-κB inhibitor, remarkably enlarged the inhibitory effect of candesartan on NF-κB pathway. In addition, M1 phenotype microglia exacerbated post-OGD N2a cells death and LDH release, whereas candesartan reversed such neurotoxic effect. Candesartan treatment may ameliorate stroke-induced neuronal damage through shifting microglia to M2 phenotype in a TLR4/NF-κB-dependent manner.



中文翻译:

坎地沙坦通过 NF-κB 信号通路调节小胶质细胞活化和极化

小胶质细胞是多种多样的细胞,它们响应于它们所处的微环境而获得不同的功能表型。已经确定了几种转录调节因子来调节不同的小胶质细胞表型。它们主要被刺激成两种相反的表型,经典 (M1) 和交替 (M2) 表型。调节从 M1 到 M2 状态的小胶质细胞极化已被认为是治疗中枢神经系统疾病的潜在治疗方法。坎地沙坦是一种血管紧张素 II I 型受体拮抗剂,具有抗氧化、抗炎、神经营养和抗凋亡功能的有益作用。然而,坎地沙坦对小胶质细胞极化的影响和潜在机制仍然未知。在这项研究中,用脂多糖(LPS)和干扰素-γ(IFN-γ)将静息的小胶质细胞刺激成M1小胶质细胞,然后用赋形剂或坎地沙坦处理24小时。RT-PCR用于检测小胶质细胞表型标志物和炎性细胞因子的mRNA表达。通过蛋白质印迹确定小胶质细胞表型标志物和 toll 样受体 4 (TLR4)/核因子κB (NF-κB) 通路。神经元-小胶质细胞共培养系统用于确定坎地沙坦是否可以改善 M1 小胶质细胞对氧-葡萄糖剥夺 (OGD) 神经元的神经毒性作用。坎地沙坦治疗降低了 M1 标志物的表达,并增加了 M2 标志物的表达。同时坎地沙坦降低了M1标志物的荧光强度和蛋白水平,增强了M2标志物。坎地沙坦还通过减少 LPS + IFN-γ 刺激的 BV2 细胞中促炎细胞因子的释放和增加抗炎细胞因子来调节神经炎症反应。坎地沙坦显着抑制 TLR4 的蛋白水平、IKBα 和 p65 的磷酸化,并抑制 NF-κB p65 的核转位。NF-κB 抑制剂 BAY 11-7085 显着增强了坎地沙坦对 NF-κB 通路的抑制作用。此外,M1 表型小胶质细胞加剧了 OGD 后 N2a 细胞死亡和 LDH 释放,而坎地沙坦逆转了这种神经毒性作用。坎地沙坦治疗可能通过以 TLR4/NF-κB 依赖性方式将小胶质细胞转变为 M2 表型来改善中风诱导的神经元损伤。坎地沙坦显着抑制 TLR4 的蛋白水平、IKBα 和 p65 的磷酸化,并抑制 NF-κB p65 的核转位。NF-κB 抑制剂 BAY 11-7085 显着增强了坎地沙坦对 NF-κB 通路的抑制作用。此外,M1 表型小胶质细胞加剧了 OGD 后 N2a 细胞死亡和 LDH 释放,而坎地沙坦逆转了这种神经毒性作用。坎地沙坦治疗可能通过以 TLR4/NF-κB 依赖性方式将小胶质细胞转变为 M2 表型来改善中风诱导的神经元损伤。坎地沙坦显着抑制 TLR4 的蛋白水平、IKBα 和 p65 的磷酸化,并抑制 NF-κB p65 的核转位。NF-κB 抑制剂 BAY 11-7085 显着增强了坎地沙坦对 NF-κB 通路的抑制作用。此外,M1 表型小胶质细胞加剧了 OGD 后 N2a 细胞死亡和 LDH 释放,而坎地沙坦逆转了这种神经毒性作用。坎地沙坦治疗可能通过以 TLR4/NF-κB 依赖性方式将小胶质细胞转变为 M2 表型来改善中风诱导的神经元损伤。M1 表型小胶质细胞加剧了 OGD 后 N2a 细胞死亡和 LDH 释放,而坎地沙坦逆转了这种神经毒性作用。坎地沙坦治疗可能通过以 TLR4/NF-κB 依赖性方式将小胶质细胞转变为 M2 表型来改善中风诱导的神经元损伤。M1 表型小胶质细胞加剧了 OGD 后 N2a 细胞死亡和 LDH 释放,而坎地沙坦逆转了这种神经毒性作用。坎地沙坦治疗可能通过以 TLR4/NF-κB 依赖性方式将小胶质细胞转变为 M2 表型来改善中风诱导的神经元损伤。

更新日期:2020-11-25
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