Myeloid cells feel the squeeze
The Piezo1 and Piezo2 proteins are excitatory ion channels used by mammalian cells to sense and respond to mechanical stimuli, but little is known about whether mechanosensors participate in immune responses. Aykut et al. investigated how modulation of Piezo1’s activity affects inflammation and immunity using agonist or antagonist compounds targeting Piezo1 along with mice lacking Piezo1 in myeloid cells. In isolated myeloid cells, Piezo1 served as the primary mechanosensory receptor. Loss of Piezo1 in myeloid cells or its global inhibition with a tarantula venom–derived peptide inhibited the differentiation of suppressive myeloid cells in mouse models of pancreatic adenocarcinoma and polymicrobial sepsis. These studies spotlight Piezo1-dependent mechanosensation as a checkpoint regulating differentiation of suppressive myeloid cells that stifle immune control of cancer and infection.
Abstract
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.
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