Oxidative stress induced TSLP production via TRPV4 regulates type 2 inflammation and pruritus in MC903 induced atopic dermatitis mouse model.

Abstract

BACKGROUND: Transient receptor potential vanilloid 4 (TRPV4) is a calcium ion channel that is widely expressed in various cells, and it regulates multiple physiological and pathological processes. In skin, TRPV4 senses temperature, mechanical and chemical stimuli. Although TRPV4 has been shown to regulate inflammatory in psoriasis, its role in atopic dermatitis (AD) remains unclear. OBJECTIVE: We aimed to elucidate the role of TRPV4 is AD pathogenesis and its potential as therapeutic target. METHODS: We used human skin samples from healthy and patients with AD for immunostaining. TRPV4 knock out (KO) mice and MC903-induced AD mouse models were used in vivo. HaCaT cells were used in vitro. RESULTS: TRPV4 was highly expressed in keratinocytes in lesional skin site of AD. TRPV4 KO mice had less severe dermatitis, barrier dysfunction and pruritus than WT mice in MC903-treated mouse model. TRPV4 KO mice had significantly decreased mRNA expression of type 2 inflammatory cytokines, including TSLP, interleukin (IL)-4, IL-13, and IL-31 via qPCR, and reduced protein levels of TSLP and IL-4 by ELISA. In vitro, oxidative stress promoted expression and activation of TRPV4, following enhanced TSLP expression in HaCaT cells. However, stimulation with IL-4 and IL-13 inhibited TRPV4 activation in HaCaT cells. Finally, treatment with selective TRPV4 antagonist HC-067047 significantly reduced the severity of MC903-induced AD-like dermatitis. CONCLUSION: Our findings showed that TRPV4 mediates the expression of keratinocyte-derived TSLP and increases Th2 immunity and pruritus, highlighting TRPV4 as a novel therapeutic strategy for the treatment of AD.