Targeting Piezo1 unleashes innate immunity against cancer and infectious disease

Berk Aykut, Ruonan Chen, Jacqueline I. Kim, Dongling Wu, Sorin A.A. Shadaloey, Raquel Abengozar, Pamela Preiss, Anjana Saxena, Smruti Pushalkar, Joshua Leinwand, Brian Diskin, Wei Wang, Gregor Werba, Matthew Berman, Steve Ki Buom Lee, Alireza Khodadadi-Jamayran, Deepak Saxena, William A. Coetzee, George Miller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbereabb5168
JournalScience immunology
Volume5
Issue number50
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Targeting Piezo1 unleashes innate immunity against cancer and infectious disease'. Together they form a unique fingerprint.

Cite this