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The regulation of polymorphonuclear leukocyte (PMN) function by mechanical forces encountered during their migration across restrictive endothelial cell junctions is not well understood. Using genetic, imaging, microfluidic, and in vivo approaches, we demonstrated that the mechanosensor Piezo1 in PMN plasmalemma induced spike-like Ca2+ signals during trans-endothelial migration. Mechanosensing increased the bactericidal function of PMN entering tissue. Mice in which Piezo1 in PMNs was genetically deleted were defective in clearing bacteria, and their lungs were predisposed to severe infection. Adoptive transfer of Piezo1-activated PMNs into the lungs of Pseudomonas aeruginosa-infected mice or exposing PMNs to defined mechanical forces in microfluidic systems improved bacterial clearance phenotype of PMNs. Piezo1 transduced the mechanical signals activated during transmigration to upregulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, crucial for the increased PMN bactericidal activity. Thus, Piezo1 mechanosensing of increased PMN tension, while traversing the narrow endothelial adherens junctions, is a central mechanism activating the host-defense function of transmigrating PMNs. 

Abstract The innate immune system plays a dual role in both mediating pathogenic processes following tissue damage and acting as a barrier to effective therapeutic delivery. Strategies that evade immune clearance while modulating host immune components offer promising solutions for treating complex chronic diseases, such as fibrosis. Here, an innate immune checkpoint material‐based strategy is presented in which mesenchymal stromal cells, coated with a soft conformal microgel and functionalized with the CD47 self‐marker agonist, effectively evade clearance by tissue resident macrophages. These engineered cells reverse persistent fibrotic damage in the lungs through a paracrine mechanism. Single‐cell RNA sequencing identifies a transitional antigen‐presenting macrophage subpopulation that mediates these reparative effects. By combining immune cloaking with the presentation of local signals encoded in the gel coatings, this strategy can be used to design secretory cells for long‐term tissue remodeling, enabling a living pharmacy for chronic tissue damage.