Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing.

1. Nat Commun. 2021 May 31;12(1):3256. doi: 10.1038/s41467-021-23482-5. Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Atcha H(1)(2), Jairaman A(3), Holt JR(3)(4), Meli VS(1)(2)(5), Nagalla RR(1)(2), Veerasubramanian PK(1)(2), Brumm KT(1)(2), Lim HE(1)(2), Othy S(3), Cahalan MD(3), Pathak MM(1)(3)(4), Liu WF(6)(7)(8). Author information: (1)Department of Biomedical Engineering, University of California Irvine, Irvine, USA. (2)The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California Irvine, Irvine, USA. (3)Department of Physiology and Biophysics, University of California Irvine, Irvine, USA. (4)Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, USA. (5)Department of Chemical and Biomolecular Engineering, University of California Irvine, Irvine, USA. (6)Department of Biomedical Engineering, University of California Irvine, Irvine, USA. wendy.liu@uci.edu. (7)The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California Irvine, Irvine, USA. wendy.liu@uci.edu. (8)Department of Chemical and Biomolecular Engineering, University of California Irvine, Irvine, USA. wendy.liu@uci.edu. Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses. DOI: 10.1038/s41467-021-23482-5 PMCID: PMC8167181 PMID: 34059671 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.