Piezo1 通道介导的 Ca2+ 信号抑制脂多糖诱导的 NF-κB 炎症信号通路激活以及小胶质细胞中 TNF-α 和 IL-6 的产生,Glia

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Piezo1 通道介导的 Ca2+ 信号抑制脂多糖诱导的 NF-κB 炎症信号通路激活以及小胶质细胞中 TNF-α 和 IL-6 的产生
Glia ( IF 5.4 ) Pub Date : 2022-11-29 , DOI: 10.1002/glia.24311
Philippa Malko ₁ , Xiaoling Jia _{1,

2} , Ian Wood ₁ , Lin-Hua Jiang _{1,

3,

4}

Affiliation

小胶质细胞在维持中枢神经系统 (CNS) 稳态和介导 CNS 疾病发病机制方面至关重要。越来越多的证据支持 CNS 微环境的机械特性的改变影响胶质细胞表型，但调节小胶质细胞功能的机制仍然难以捉摸。在这里，我们使用 BV2 和原代小胶质细胞检查了小胶质细胞中的机械敏感 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 mRNA 和蛋白质水平上检测到小胶质细胞中的 Piezo1 表达。Piezo1 通道激活剂 Yoda1 诱导 Ca ²⁺通量增加细胞内 Ca ^2+的应用通过用钌红、一种 Piezo1 抑制剂或 Piezo1 特异性 siRNA 处理降低了浓度，支持 Piezo1 作为细胞表面 Ca ²⁺可渗透通道发挥作用。用脂多糖 (LPS) 引发诱导小胶质细胞活化和 TNF-α 和 IL-6 的产生，这些被 Yoda1 处理抑制。此外，LPS 引发诱导了 ERK、p38 MAPK 和 NF-κB 的激活。LPS 诱导的 NF-κB 激活，但 ERK 和 p38 激活不受 Yoda1 处理的抑制。Yoda1 诱导的抑制被 siRNA 介导的 Piezo1 表达耗竭减弱，此外，用 BAPTA-AM 处理以防止细胞内 Ca ²⁺增加。^{总的来说，我们的结果支持 Piezo1 通道激活通过启动细胞内 Ca 2+}信号以抑制 NF-κB 炎症信号通路来下调小胶质细胞的促炎功能，尤其是 TNF-α 和 IL-6 的产生。这些发现揭示了 Piezo1 通道激活是一种以前未被认识的调节小胶质细胞功能的机制，为靶向这种分子机制以减轻神经炎症和相关的 CNS 病理提供了一个有趣的视角。

"点击查看英文标题和摘要"

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

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-α and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-κB. LPS-induced activation of NF-κB, 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-α and IL-6, by initiating intracellular Ca²⁺ signaling to inhibit the NF-κB 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.

更新日期：2022-11-29

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