Current Insights Into the Role of Neuropeptide Y in Skin Physiology and Pathology.

Neuropeptide Y is widely distributed within the body and has long been implicated as a contributor to skin disease based on the correlative clinical data. However, until recently, there have been few empirical investigations to determine whether NPY has a pathophysiological role in the skin. Due to appearance-altering phenotypes of atopic dermatitis, psoriasis, and vitiligo, those suffering from these diseases often face multiple forms of negative social attention. This often results in psychological stress, which has been shown to exacerbate inflammatory skin diseases - creating a vicious cycle that perpetuates disease. This has been shown to drive severe depression, which has resulted in suicidal ideation being a comorbidity of these diseases. Herein, we review what is currently known about the associations of NPY with skin diseases and stress. We also review and provide educated guessing what the effects NPY can have in the skin. Inflammatory skin diseases can affect physical appearance to have significant, negative impacts on quality of life. No cure exists for these conditions, highlighting the need for identification of novel proteins/neuropetides, like NPY, that can be targeted therapeutically. This review sets the stage for future investigations into the role of NPY in skin biology and pathology to stimulate research on therapeutic targeting NPY signaling in order to combat inflammatory skin diseases.

A novel mouse model to evaluate neuropeptide Y-mediated melanocyte pathology.

Vitiligo is an autoimmune disease characterized by depigmented patches of skin due to loss of the pigment-producing melanocytes. No cure exists for vitiligo. The available treatments are inefficient for many patients, suggesting that universal treatment approaches may be inappropriate. Deeper understanding of the mechanistic basis for variability in vitiligo aetiologies is necessary. Genetic mutations in neuropeptide Y (NPY), a widely distributed protein, are associated with increased NPY expression and increased susceptibility for vitiligo. NPY is also upregulated in the circulation and lesional skin of some vitiligo patients. However, the contributions of NPY to melanocyte pathology are not understood, and presently there are no models with which to investigate this possibility. In this study, we employed NPY-overexpressing mice to explore the role of NPY in melanocyte dysfunction. Our results show that NPY overexpression induces progressive hair greying (depigmentation) due to premature depletion of follicular melanocyte stem cells. Additionally, NPY transcripts and protein are elevated in the skin and melanocytes of these mice, respectively, suggesting that these effects may be mediated locally. Together, these results suggest that supraphysiological levels of NPY in the skin can induce melanocyte dysfunction, thus identifying this mouse line as a novel model to study NPY-mediated melanocyte pathology.

Topical RT1640 treatment effectively reverses gray hair and stem cell loss in a mouse model of radiation-induced canities.

Gray hair is a visible sign of tissue degeneration during aging. Graying is attributed to dysfunction of melanocyte stem cells (McSCs) that results in depletion of their melanin-producing progeny. This non-lethal phenotype makes the hair follicle and its pigment system an attractive model for investigating mechanisms that contribute to tissue aging and therapeutic strategies to combat this process. One potential combination therapeutic is RT1640, which is comprised of two drugs that are known to stimulate hair growth (cyclosporine A [CsA] and minoxidil), along with RT175, a non-immunosuppressive immunophilin ligand that is implicated in tissue regeneration. Using the ionizing radiation-induced acute mouse model of hair graying, we demonstrate that RT1640, over CsA alone, promotes regeneration of the hair pigment system during and following treatment. In non-irradiated mice, RT1640 is also physiologically active and successfully speeds hair growth and expands the McSC pool. It appears that this effect relies on the combined activities of the three drugs within RT1640 to simultaneously activate hair growth and McSCs as RT175 alone was insufficient to induce hair cycling in vivo, yet sufficient to drive the upregulation of the melanogenic program in vitro. This study sets the stage for further investigation into RT1640 and its components in McSC biology and, ultimately, melanocyte hypopigmentary disorders associated with disease and aging.