TRPV1 expression is upregulated in subjects with sensitive skin, and it correlates with the intensity of the symptoms. Our findings suggest a role for this receptor in the pathogenesis of sensitive skin syndrome.

The pathogenesis of melasma, a common, photo-induced hyperpigmentary disorder, is not clearly understood. Significant factors linked to melasma are ultraviolet radiation exposure and genetic predisposition. Histological analysis has demonstrated that melasma is caused by a network of cellular interactions among melanocytes, keratinocytes, mast cells, fibroblasts, and dermal vasculature exhibits, features similar to chronic sun damage. Dermal inflammation caused by ultraviolet radiation might play an important role in the hyperpigmentation and reactivation of melasma lesions through the production of melanogenic cytokines and growth factors. Because the role of inflammation in this disorder is unknown, we used histochemistry, immunohistochemistry, and quantitative real-time polymerase chain reaction to evaluate melasma lesions from healthy female patients (n = 20) with malar melasma. Lesional skin without specific solar exposure or photoprotection measures within the previous 4 weeks was compared with nonlesional skin. The increased lymphocytic infiltrate in lesional skin was mainly composed of CD4 T cells, mast cells, and macrophages. Levels of the cytokine interleukin (IL)-17 and the proinflammatory mediator cyclooxygenase (COX)-2 were significantly elevated in affected skin compared with healthy skin. In addition, the Melasma Activity and Severity Index score, fraction of solar elastosis, and epidermal melanin were positively associated with COX-2 expression. There was no statistically significant difference in IL-1α, IL-1β, R-IL1, IL-6, IL-8, vascular endothelial growth factor, and tumor necrosis factor alpha expression levels. Together, these data indicated that melasma under unchallenged conditions is characterized by chronic inflammatory cells and mediators, which may explain its recurrent nature.

SASH1 has recently been identified as a novel pigmentation gene. Mutations in SASH1 cause inherited pigmentation disorders including lentigines, a common form of hyperpigmentation in human skin. Studying the function of SASH1 and associated disorders will likely lead to new insight to melanocyte biology and pathological mechanisms for pigmentation disorders. Many inherited lentigines have increased melanocyte proliferation through activation of the RAS/RAF/MAPK signaling. Our histological examination of skin biopsies from SASH1 mutation affected individuals showed increased numbers of melanocytes; however, no obvious increases in proliferating melanocytes were observed. Melanocyte-derived cell culture transfection and stable transduction showed that overexpressing wild type of mutated SASH1 did not alter MAPK signaling and the mutation in SASH1 did not increase proliferation or survival. Conversely, knockdown of SASH1 in melanocyte-lineage cells altered cell morphology and induced pigmentation production, consistent with more differentiated status. Furthermore, clinical examination identified that affected individuals displayed premature hair graying as young adults, strongly supporting aberrant differentiation as a pathological mechanism. To characterize the molecular mechanisms better, we are currently using multiple patient-specific iPSC clones and functional melanocytes from two affected individuals, and multiple gene-corrected isogenic iPSC clones. In sum, we identified hair graying as a new phenotype associated with SASH1-mediated disorders and aberrant differentiation of melanocyte lineage as a potential new mechanism for pigmentation disorders.

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