Transient receptor potential vanilloid (TRPV) 억제와 염증성 과색소침착의 치료

Abstract

Background and Objectives: Pigmented contact dermatitis (PCD) is a skin disorder caused by inflammation-related hyperpigmentation. Little is known of the pathogenesis of PCD, making its treatment quite challenging. Patients with PCD often report pruritus and burning sensation on affected areas. These clinical features suggest the possible role of transient receptor potential vanilloid (TRPV) channels in the pathogenesis of PCD as these calcium-modulating channels participate in diverse processes such as neurogenic inflammation, perception of pain and itch, and even cutaneous melanogenesis. Therefore, we sought to evaluate the expression level of TRPVs in the skin of patients with PCD aiming at identifying crucial receptors related to inflammation-associated melanogenesis.

Methods: Immunohistochemical analysis was performed to evaluate cutaneous expression of TRPVs in PCD patients’ lesional skin in comparison to the corresponding peri-lesional skin. The mRNA levels of various melanogenesis-related genes were measured using Next-generation sequencing (NGS). Capsaicin, a potent TRPV1 activator, and AMG9810, a selective TRPV1 inhibitor, were used as TRPV regulators in in vitro assays using normal human melanocytes. The expression of melanogenesis-related proteins was assessed using Western blot assay.

Results: TRPVs were increased in the epidermal and dermal cells in the lesions of PCD. Furthermore, Pmel, TYRP1 and S100A8 were increased in the lesions of PCD compared to peri-lesion. qRT-PCR analysis showed that tyrosinase, along with TRPV1 and TRPV3, was up-regulated in patients with PCD. We also demonstrated that TRPV1 regulates melanogenesis in human melanocytes as well as B16 melanoma cells and co-culture. TRPV1 activation promoted melanin synthesis in human melanocytes in vitro, while this effect could be reversed by TRPV1 blockade using AMG9810. A notable downmodulation of PKC-βII signaling was observed, subsequently decreasing the activity of tyrosinase. This resulted in the anti-melanogenic effect of TRPV1 inhibitors.

Conclusion: Our findings suggest that elevated expression of TRPVs in the skin links the clinically reported symptoms of PCD to its causative inflammation-related hyperpigmentation. TRPVs, particularly TRPV1, may play a crucial role in the development, aggravation and chronicity of PCD through modulation of ca2+/PKC/tyrosinase activity.