Participation of keratinocyte- and fibroblast-derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders

Abstract

Human epidermal melanocytes play a central role in sensing the environment and protecting the skin from the drastic effects of solar ultraviolet radiation and other environmental toxins or inflammatory agents. Melanocytes survive in the epidermis for decades, which subjects them to chronic environmental insults. Melanocytes have a poor self-renewal capacity; therefore, it is critical to ensure their survival with genomic stability. The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes and dermal fibroblasts. A symbiotic relationship exists between epidermal melanocytes and keratinocytes on the one hand, and between melanocytes and dermal fibroblasts on the other hand. Melanocytes protect epidermal keratinocytes and dermal fibroblasts from the damaging effects of solar radiation, and the latter cells synthesize biochemical mediators that maintain the homeostasis, and regulate the stress response of melanocytes. Disruption of the paracrine network results in pigmentary disorders, due to abnormal regulation of melanin synthesis, and compromise of melanocyte survival or genomic stability. This review provides an update of the current knowledge of keratinocyte- and fibroblast-derived paracrine factors and their contribution to melanocyte physiology, and how their abnormal production is involved in the pathogenesis of common pigmentary disorders.

Keywords: DNA damage response; melanocytes; paracrine factors; pigmentary disorders; solar UV.

FIGURE 1

List of the major paracrine factors synthesized by keratinocytes, their receptors, and biological effects on melanocyte survival, proliferation, and melanogenesis

FIGURE 2

Participation of α-MSH, End-1, NGF, and vitamin D in the DNA damage response to UV, which results in reduced DNA photoproducts by activating NER, oxidative DNA damage by upregulating BER and antioxidant genes, and apoptosis, by increasing Bcl2 levels, thereby maintaining melanocyte survival and genomic stability. BER, base excision repair; NER, nucleotide excision repair

FIGURE 3

List of the known fibroblast-derived paracrine factors, and the biological effects of these factors via their receptors and of ECM on melanocyte proliferation and melanogenesis. ECM, extracellular matrix