Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene Rb1. We further show that Piezo1-mediated silencing of Rb1 is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.

Piezo1 是一种机械敏感离子通道，因其在调节多种生理过程中的作用而获得认可。然而，Piezo1 在炎症性疾病中的影响，包括感染和肿瘤免疫，尚未得到很好的研究。我们假设 Piezo1 将物理力与骨髓细胞的免疫调节联系起来。我们在骨髓细胞中发现了通过 Piezo1 的信号转导，并将该通道建立为这些细胞中机械应力的主要传感器。用肽抑制剂全面抑制 Piezo1 可预防癌症和感染性休克，并导致抑制性骨髓细胞减少。此外，删除Piezo1在骨髓细胞中保护免受癌症并增加多微生物败血症的存活率。从机制上讲，我们表明机械刺激通过抑制成视网膜细胞瘤基因Rb1来促进 Piezo1 依赖性骨髓细胞增殖。我们进一步表明，Piezo1 介导的Rb1沉默是通过组蛋白去乙酰化酶 2 的上调来调节的。总的来说，我们的工作发现 Piezo1 作为可靶向的免疫检查点，在癌症和传染病中驱动免疫抑制性骨髓细胞生成。