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 response¹. 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 cues². Here using reverse genetics, we show that myeloid cells respond to force and alterations in cyclical hydrostatic pressure via the mechanosensory ion channel PIEZO1³. 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 infiltrating monocytes respond to cyclical force to recruit neutrophils and clear pulmonary Pseudomonas aeruginosa infection via EDN1. Furthermore, myeloid PIEZO1 also drove lung pathology in a mouse model of pulmonary fibrosis. Our results demonstrate a novel environmental sensory axis that myeloid cells recognize to mount an inflammatory response and is the first report showing a physiological role for PIEZO1 and mechanosensation in immunity.