No abstract

No abstract

Although cells of the immune system experience force and pressure throughout their lifecycle, almost nothing is known about how these mechanical processes regulate the immune response 1. Both tissue-resident and tissue-infiltrating immune cells in highly mechanical organs, such as the lung, are constantly exposed to tonic and dynamically changing mechanical cues 2. Here using reverse genetics, we show that myeloid cells respond to force and alterations in cyclical hydrostatic pressure via the mechanosensory ion channel PIEZO1 3. Unbiased RNA sequencing from macrophages subjected to cyclical hydrostatic pressure reveals a striking state of proinflammatory reprogramming. We report a novel mechanosensory-immune signaling circuit which PIEZO1 initiates in response to cyclical hydrostatic pressure, driving c-JUN activation and transcriptional upregulation of Endothelin-1 (EDN1). EDN1 in turn stabilizes HIF1α, which facilitates transcription of a potent and prolonged program of proinflammatory mediators. Using mice conditionally deficient of PIEZO1 in myeloid cells, and cellular depletion assays, we show 10

VE-cadherin plays a critical role in endothelial shear stress mechanotransduction by interacting with VEGFRs through their transmembrane domains.

SummaryForces acting on cells govern many important regulatory events during development, normal physiology, and disease processes. Integrin-mediated adhesions, which transmit forces between the extracellular matrix and the actin cytoskeleton, play a central role in transducing effects of forces to regulate cell functions. Recent work has led to major insights into the molecular mechanisms by which these adhesions respond to forces to control cellular signaling pathways. We briefly summarize effects of forces on organs, tissues, and cells; and then discuss recent advances toward understanding molecular mechanisms.