Oxidative stress-induced activation of transient receptor potential vanilloid 4 (trpv4) may regulate type 2 immunity and pruritus in mc903-induced atopic dermatitis mouse model.

Summary: Abstract Body: Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP channel family, is highly expressed in the skin and plays diverse roles, including chemical sensing, cell proliferation, and immune responses in multiple organs. Recently, we found increased TRPV4 expression in the lesional skin of patients with atopic dermatitis (AD). However, its precise role in AD pathogenesis remains unclear. This study aimed to elucidate the role of TRPV4 in AD using an MC903-induced AD model in wild type (WT) and TRPV4 knockout (KO) mice. Our results demonstrated that dermatitis score (p = 0.02), TEWL (p = 0.02), and scratching behavior (p = 0.03) were significantly reduced in TRPV4 KO mice compared to WT mice. Histopathological analysis revealed significantly fewer infiltrating CD4+ T cells and mast cells in TRPV4 KO mice. FACS analysis of skin tissue confirmed a reduced number of CD45+CD4+IL-4+ cells in TRPV4 KO mice compared with WT mice. The qPCR analysis showed decreased mRNA levels of Th2 cytokines, including TSLP, IL-4, IL-13, and IL-31, in TRPV4 KO mice compared with WT mice. Treatment with TRPV4 antagonist also significantly improved dermatitis score, TEWL, scratching behavior, and suppressed TSLP and IL-4 mRNA expression in MC903-treated mice. In vitro experiment revealed that oxidative stress induced by hypoxia or hydrogen peroxide stimulation increased TRPV4 expression in HaCaT cells. Moreover, siRNA-mediated TRPV4 knockdown suppressed TSLP production. In conclusion, our findings suggest that TRPV4, possibly activated by oxidative stress, regulate type 2 inflammation and pruritus through TSLP production and inflammatory cell infiltration in MC903-induced AD-like dermatitis. TRPV4 may serve as a potential therapeutic target for pruritic dermatitis, such as AD and prurigo. Keiji Kosaka¹, Akihiko Uchiyama¹, Syahla N. Amalia¹, Yuta Inoue¹, Mai Ishikawa¹, Yoko Yokoyama¹, Sachiko Ogino¹, Yuki Watanuki¹, Ryoko Torii¹, Sei-ichiro Motegi¹ 1. Dermatology, Gunma Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Maebashi, Gunma Prefecture, Japan. Adaptive and Auto-Immunity