Zhu Ting, Guo Jinghui, Wu Yong, Lei Ting, Zhu Jiejun, Chen Hui, Kala Shashwati, Wong Kin Fung, Cheung Chi Pong, Huang Xiaohui, Zhao Xinyi, Yang Minyi, Sun Lei
Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR 999077, P. R. China.
Biotherapy Centre, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
iScience. 2023 Jan 16;26(2):105993. doi: 10.1016/j.isci.2023.105993. eCollection 2023 Feb 17.
Microglia are the brain's resident immune cells, performing surveillance to promote homeostasis and healthy functioning. While microglial chemical signaling is well-studied, mechanical cues regulating their function are less well-understood. Here, we investigate the role of the mechanosensitive ion channel Piezo1 in microglia migration, pro-inflammatory cytokine production, and stiffness sensing. In Piezo1 knockout transgenic mice, we demonstrated the functional expression of Piezo1 in microglia and identified genes whose expression was consequently affected. Functional assays revealed that Piezo1 deficiency in microglia enhanced migration toward amyloid β-protein, and decreased levels of pro-inflammatory cytokines produced upon stimulation by lipopolysaccharide, both and . The phenomenon could be mimicked or reversed chemically using a Piezo1-specific agonist or antagonist. Finally, we also showed that Piezo1 mediated the effect of substrate stiffness-induced migration and cytokine expression. Altogether, we show that Piezo1 is an important molecular mediator for microglia, its activation modulating microglial migration and immune responses.
小胶质细胞是大脑中的常驻免疫细胞，执行监测功能以促进体内平衡和健康运作。虽然小胶质细胞的化学信号传导已得到充分研究，但调节其功能的机械信号却鲜为人知。在此，我们研究机械敏感离子通道Piezo1在小胶质细胞迁移、促炎细胞因子产生和硬度感知中的作用。在Piezo1基因敲除转基因小鼠中，我们证明了Piezo1在小胶质细胞中的功能性表达，并鉴定了其表达因此受到影响的基因。功能测定表明，小胶质细胞中Piezo1的缺失增强了向淀粉样β蛋白的迁移，并降低了脂多糖刺激后产生的促炎细胞因子水平。使用Piezo1特异性激动剂或拮抗剂可以化学模拟或逆转这种现象。最后，我们还表明Piezo1介导了底物硬度诱导的迁移和细胞因子表达的作用。总之，我们表明Piezo1是小胶质细胞的重要分子介质，其激活调节小胶质细胞迁移和免疫反应。
