Targeting Piezo1 unleashes innate immunity against cancer and infectious disease

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.

Crosstalk Between CD11b and Piezo1 Mediates Macrophage Responses to Mechanical Cues

“…Influx of Ca 2+ through ion channels has been shown to play important roles in regulating macrophage activation and adhesion ( 28 , 41 , 42 ). Of these channels, Piezo1 has recently been shown to be highly expressed in macrophages and is known to sense and transduce cyclic hydrostatic pressure, shear stresses, and stiffness, while also regulating macrophage inflammatory activation ( 28 , 33 – 35 ). To evaluate the role of Piezo1 in regulating stretch-mediated macrophage inflammatory responses we examined Piezo1 expression, and modulated Piezo1 activity or expression using pharmacologic and genetic approaches.…”

“…A few recent studies including our own work have identified a role for Piezo1 in mechanosensation of hydrostatic pressure, fluid shear stress, and environmental stiffness in myeloid cells ( 28 , 33 , 34 ). Piezo1 activity was also found to promote inflammation ( 28 , 33 , 35 ). However, the role of integrins, Piezo1, and the interplay between these molecules in macrophages, specifically in the context of stretch mechanotransduction is yet to be studied.…”

Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4 + T cell responses

“…In monocytes, Piezo1 channels sense cyclical mechanical forces in the lung and are required to mount proinflammatory responses in a mouse model of Pseudomonas infection (22). Expression of Piezo1 is also associated with expansion of myeloid-derived suppressor cells, leading to tumor progression in a mouse cancer model (23). These studies raise intriguing questions about the regulatory role of Piezo1 in normal adaptive immune functions and in autoimmunity.…”

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

“…While increased Ca 2+ influx through transient receptor potential (TRP) channels, including TRPM7 and TRPC1, is widely recognized to contribute to macrophage activation by inflammatory agonists 25,26 , the role of Piezo1 and the Ca 2+ signals it generates in response to soluble stimuli remains less well explored. Recent studies have identified Piezo1 as a mechanosensor of pressure and shear stress in myeloid cells recruited to the lung, heart, and tumors, and found that channel activity stimulates inflammation [27][28][29] . However, macrophages in most tissues are not subjected to such extreme mechanical stresses, and the mechanical cue that all macrophages are likely to encounter in their environment is variations in matrix stiffness.…”