Piezo1 Remodels Macrophage Stiffness For Host Defense

Macrophages encounter different mechanical cues to adapt their behaviors to the microenvironment in both health and disease.However,whether and how cellular mechanical property determines innate response remains largely unclear.Here we report that the mechanical sensor Piezo1 remodels macrophage stiffness in response to various biochemical cues for host defense.Bacterial infection or stimulation of various soluble pathogen-associated molecular patterns(PAMPs)promote F-actin reorganization and remodel macrophage stiffness for mitochondrion-phagosome juxtaposition,ROS production and bacterial clearance.Furthermore,we found that Piezo1 activated by Piezol’s agonist Yodal treatment or the extracellular matrix(ECM)rigidity can further promote these phenotypes for host defense.While knockout of Piezol abrogates all these responses.Mechanistically,Piezol regulates macrophage mechanobiology through calcium signal-induced actication of the Hippo signaling pathway.Consistently,inhibition or knockout of Mst1/2 in macrophages phenocopy Piezol deficiency.Thus,we conclude that Piezo1 translates extracellular physical and chemical cues into cellular mechano-response and drives innate immunity for host defense,providing critical insight for understanding macrophage mechanophysiology.