Shear Stress as a Danger Signal: Inducing Inflammation and Thrombosis via Mechanosensitive NETosis

ABSTRACT Neutrophil extracellular traps (NETs)—web‐like DNA structures extruded by neutrophils in response to various stimuli, including pathogens, sterile inflammation, and mechanical stress—play a dual role in immunity and disease. While NETs serve to trap and neutralize pathogens during host defense, excessive or dysregulated NET formation, known as NETosis, can amplify inflammation and contribute to thrombotic complications such as atherosclerosis and valve disease. Increasing evidence supports that NETosis is a regulated, signaling‐driven process, and that mechanical forces—including shear stress, tensile force, and matrix stiffness—can act as noncanonical danger signals capable of inducing NETosis. Mechanosensitive ion channels such as Piezo1, have emerged as key transducers of these biophysical cues, enabling cells to convert changes in shear stress levels into intracellular calcium flux, cytoskeletal remodeling, and ultimately NET release. Furthermore, exposure to pathologically high levels of shear stress may improve the sensitivity of neutrophils to secondary stimuli, lowering their activation threshold and amplifying inflammatory and thrombotic cascades. This mechanosensitive framework highlights shear‐induced NETosis as a critical pathway by which neutrophils contribute to inflammation and thrombosis in mechanically stressed vascular environments.