078 TRPV4 regulates the IL-23/Th17 pathways in imiquimod-induced psoriasis-like lesion through the production of ATP and neuropeptide

Psoriasis is a chronic inflammatory skin disease with a complex mechanism that involves the activity of different type of cells. Along with the IL-23/Th17 axis, the nervous system plays an important role in the development of psoriasis. Transient receptor potential vanilloid 4 (TRPV4) ion channel is Ca2+-permeable nonselective cation channels that express in keratinocytes, nerve fibers, and immune cells in the skin. Recently, we found an increased expression of TRPV4 in human psoriasis skin site. We hypothesized that the activation of TRPV4 channel would play a significant role in the development of psoriasis. The objective was to investigate TRPV4 involvement in the pathogenesis of psoriasis. Imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was utilized in wild type and TRPV4 knockout (KO) mice. The severity of skin dermatitis was significantly lower in TRPV4 KO mice compared to WT mice from day 3 to 6 (p<0.01). Histopathological studies showed that the epidermal thickness and the number of infiltrated CD3+ T cells and CD68+ macrophages were significantly reduced in KO mice, along with the expression of IL-17A, IL-17F and IL-23 (p<0.05 for each). Moreover, the level of ATP and the expression of neuropeptides, such as Substance P, Calcitonin gene-related peptide, and neuron marker PGP9.5 in KO mouse were significantly decreased (p <0.05). The proliferative capacity and the production of heat or air-stimulated ATP in TRPV4-deficient keratinocytes were significantly inhibited in vitro. Finally, the administration of TRPV4 antagonist (HC-067047) significantly prevented the development of psoriasis-like dermatitis in IMQ-treated mice. In conclusion, TRPV4 might involve in the activation of IL-23/Th17 axis through the production of ATP and neuropeptides and increase the proliferation of keratinocyte. TRPV4 might have the potential to be a new therapeutic target in psoriasis.