639 Regulatory function of TRPV4 on the dermal component of inflammatory skin conditions

Abstract

Several skin-expressed Transient Receptor Potential (TRP) channels act as sensors of temperature, mechanical, and chemical stimuli. In the skin, TRPV4 is expressed in many nonneuronal cell populations including keratinocytes, immune cells and on skin appendages. This thermo- and osmosensitive protein has a high impact on the epidermal barrier, regulation of hair growth and sebum production and the secretion of inflammatory cytokines. Since we have less information about the role of TRPV4 in the dermis we aimed to investigate the functional presence of TRPV4 on human dermal fibroblasts (FB). First, we showed that TRPV4 is expressed on FBs both on mRNA and protein levels. We found that both osmotic- (using hyposmotic conditions) and pharmacological activation - by the specific agonist GSK1016790A - of TRPV4 resulted an increased Ca2+[IC] level on human FBs. This effect was inhibited by the specific antagonist of TRPV4, HC-067047. Next we examined the effect of TRPV4 activation on the expression of different regulatory genes which are implicated in collagen synthesis, inflammatory processes (interleukins and growth factors) and extracellular matrix remodelling. We found that TRPV4 significantly influenced the expression profile of these genes. Of particular note GSK1016790A exerted remarkable proinflammatory effects by inducing elevated interleukin-8 (IL-8) cytokine release. Since IL-8 is a chemoattractant we performed an invasion assay on FBs and the activation of TRPV4 resulted in higher migration activity of FBs, moreover the collected supernatant from these FBs increased the human keratinocyte proliferation. In all cases these effects were abrogated by HC-067047. These findings indicate that TRPV4 may be a key regulator of FBs biological processes. Therefore, pharmacological modulation of TRPV4 could be a promising tool for the management of wound healing, skin remodelling, fibrosis and skin-related inflammatory conditions.