Abstract
Mechanical forces shape immune responses in both health and disease. PIEZO1 and PIEZO2, two mechanosensitive ion channels, have emerged as critical transducers of these forces, influencing inflammation, pain, fibrosis, and neuroimmune regulation. This review aims to synthesize the current evidence on the role of PIEZO channels in mechano-inflammation, with a specific focus on their regulatory function in neuroimmune crosstalk. A comprehensive narrative synthesis was performed using the literature from PubMed, Scopus, and Web of Science up to June 2025. Experimental, translational, and mechanistic studies involving PIEZO channels in inflammatory, fibrotic, and neuroimmune processes were included. PIEZO1 is broadly expressed in immune cells, fibroblasts, and endothelial cells, where it regulates calcium-dependent activation of pro-inflammatory pathways, such as NF-kB and STAT1. PIEZO2, enriched in sensory neurons, contributes to mechanosensory amplification of inflammatory pain. Both channels are mechanistically involved in neuroinflammation, glial activation, blood-brain barrier dysfunction, connective tissue fibrosis, and visceral hypersensitivity. PIEZO channels act as integrators of biomechanical and immunological signaling. Their roles as context-dependent gatekeepers of neuroimmune crosstalk make them attractive targets for novel therapies.