Piezo1 channel-mediated Ca2+ signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells
Piezo1 channel-mediated Ca2+ signaling inhibits lipopolysaccharide-induced activation of the NF-κB inflammatory signaling pathway and generation of TNF-α and IL-6 in microglial cells
复制标题
Piezo1 通道介导的 Ca2 信号传导抑制脂多糖诱导的 NF-κB 炎症信号传导途径的激活以及小胶质细胞中 TNF-α 和 IL-6 的生成
DOI：
10.1002/glia.24311
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发表时间：
2022-11-29
期刊：
影响因子：
6.2
通讯作者：
Jiang, Lin-Hua
中科院分区：
文献类型：
--
作者：
Malko, Philippa;Jia, Xiaoling;Jiang, Lin-Hua
小胶质细胞在维持中枢神经系统(CNS)内环境平衡和介导CNS疾病发病机制中起着至关重要的作用。越来越多的证据支持，中枢神经系统微环境机械特性的改变会影响神经胶质细胞的表型，但调节小胶质细胞功能的机制仍然不清楚。在这里，我们使用BV2和原代小胶质细胞，研究了小胶质细胞中机械敏感的Piezo1通道，特别是Piezo1通道激活如何调节促炎激活和促炎细胞因子的产生。在小胶质细胞中检测到PIEZO1在mRNA和蛋白水平的表达。应用Piezo1通道激活剂Yoda1诱导细胞内钙离子流量增加，而Piezo1抑制剂Ru红或Piezo1特异性siRNA处理后细胞内钙离子浓度降低，支持Piezo1作为细胞表面钙离子通透通道的功能。脂多糖诱导小胶质细胞活化，产生肿瘤坏死因子-α和白介素6，尤达1号对此有抑制作用。此外，内毒素可诱导ERK、p38MAPKs和核因子-kappaB的激活。Yoda1可抑制内毒素诱导的核因子-kappaB的激活，但不抑制ERK和p38的激活。通过siRNA抑制Piezo1的表达，BAPTA-AM可抑制Yoda1诱导的细胞内钙浓度升高。总之，我们的结果支持，Piezo1通道的激活通过启动细胞内钙信号来抑制核因子-kappa B炎症信号通路，从而下调小胶质细胞的促炎功能，特别是TNF-α和IL-6的产生。这些发现揭示了Piezo1通道激活是一种先前未知的调节小胶质细胞功能的机制，为靶向这一分子机制以减轻神经炎症和相关的中枢神经系统病理提供了一个有趣的视角。
Microglial cells are crucial in maintaining central nervous system (CNS) homeostasis and mediating CNS disease pathogenesis. Increasing evidence supports that alterations in the mechanical properties of CNS microenvironments influence glial cell phenotypes, but the mechanisms regulating microglial cell function remain elusive. Here, we examined the mechanosensitive Piezo1 channel in microglial cells, particularly, how Piezo1 channel activation regulates pro-inflammatory activation and production of pro-inflammatory cytokines, using BV2 and primary microglial cells. Piezo1 expression in microglial cells was detected both at mRNA and protein levels. Application of Piezo1 channel activator Yoda1 induced Ca2+ flux to increase intracellular Ca2+ concentration that was reduced by treatment with ruthenium red, a Piezo1 inhibitor, or Piezo1-specific siRNA, supporting that Piezo1 functions as a cell surface Ca2+-permeable channel. Priming with lipopolysaccharide (LPS) induced microglial cell activation and production of TNF-alpha and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-kappa B. LPS-induced activation of NF-kappa B, but not ERK and p38, was inhibited by treatment with Yoda1. Yoda1-induced inhibition was blunted by siRNA-mediated depletion of Piezo1 expression and, furthermore, treatment with BAPTA-AM to prevent intracellular Ca2+ increase. Collectively, our results support that Piezo1 channel activation downregulates the pro-inflammatory function of microglial cells, especially production of TNF-alpha and IL-6, by initiating intracellular Ca2+ signaling to inhibit the NF-kappa B inflammatory signaling pathway. These findings reveal Piezo1 channel activation as a previously unrecognized mechanism regulating microglial cell function, raising an interesting perspective on targeting this molecular mechanism to alleviate neuroinflammation and associated CNS pathologies.