Dual function of TRPV4 in chronic dermatitis: Barrier protection counterbalanced by pruritic scratching

Chronic dermatitis represents a debilitating inflammatory skin disorder characterized by intense pruritus and significant epidermal barrier dysfunction that seriously deteriorates the quality of life of patients. Damage to the skin barrier plays a critical role in the development and progression of chronic dermatitis, while the expression of tight junction proteins is essential for maintaining barrier function. TRPV4, a mechano- and thermosensitive ion channel abundantly expressed in keratinocytes, has been implicated in both pruriceptive signaling and keratinocyte function, yet its role in maintaining barrier integrity during chronic dermatitis remains undefined. Here, we confirmed the high expression of Trpv4 in HaCaT cells and demonstrated its predominant expression in HaCaT cells and primary keratinocytes through calcium imaging studies that revealed robust, TRPV4-specific calcium responses to agonist stimulation. Using pharmacological and genetic approaches, we found that TRPV4 activation significantly enhanced tight junction proteins expression under physiological condition. Intriguingly, in conventional oxazolone-induced nape chronic dermatitis model, Trpv4 deficiency failed to alter tight junction protein expression, masking its potential barrier-protective effects. However, when we eliminated scratching interference by establishing a back-localized chronic dermatitis model, Trpv4 knockout mice exhibited significantly exacerbated skin lesions accompanied by reduced expression of tight junction proteins. Our results suggest that TRPV4 represents a dual-edged sword in skin pathology, and its exploitation as a therapeutic target in CD necessitates a "dual-track" strategy that pairs barrier-boosters with potent anti-pruritic interventions to break the cycle of self-perpetuating damage.