Emerging roles of mechanically activated ion channels in autoimmune disease

Abstract

Mechanically activated (MA) ion channels have rapidly gained prominence as vital conduits bridging aberrant mechanical cues in tissues with the dysregulated immune responses at the core of autoimmune diseases. Once regarded as peripheral players in inflammation, these channels, exemplified by PIEZO1, TRPV4, and specific K2P family members, now play a central role in modulating T-cell effector functions, B- cell activation and the activity of macrophages and dendritic cells. Their gating is intimately tied to physical distortions such as increased tissue stiffness, osmotic imbalances, or fluid shear, triggering a cascade of ionic fluxes that elevate proinflammatory signaling and drive tissue-destructive loops. Recognition of these channels as central mediators of mechanical stress-induced inflammation responses in autoimmune pathogenesis is rapidly expanding. In parallel, the emerging therapeutic strategies aim to restrain overactive mechanosensors or selectively harness them in affected tissues. Small molecules, peptide blockers, and gene-targeting approaches show preclinical promise, although off-target effects and the broader homeostatic roles of these channels warrant caution. This review explores how integrating mechanobiological concepts with established immunological paradigms enables a more detailed understanding of autoimmune pathogenesis. By elucidating how mechanical forces potentiate or dampen pathological immunity, we propose innovative strategies that exploit mechanosensitivity to recalibrate immune responses across a spectrum of autoimmune conditions.