Recognition of Melanocytes in Immuno-Neuroendocrinology and Circadian Rhythms: Beyond the Conventional Melanin Synthesis

Abstract

Melanocytes produce melanin to protect the skin from UV-B radiation. Notwithstanding, the spectrum of their functions extends far beyond their well-known role as melanin production factories. Melanocytes have been considered as sensory and computational cells. The neurotransmitters, neuropeptides, and other hormones produced by melanocytes make them part of the skin’s well-orchestrated and complex neuroendocrine network, counteracting environmental stressors. Melanocytes can also actively mediate the epidermal immune response. Melanocytes are equipped with ectopic sensory systems similar to the eye and nose and can sense light and odor. The ubiquitous inner circadian rhythm controls the body’s basic physiological processes. Light not only affects skin photoaging, but also regulates inner circadian rhythms and communicates with the local neuroendocrine system. Do melanocytes “see” light and play a unique role in photoentrainment of the local circadian clock system? Why, then, are melanocytes responsible for so many mysterious functions? Do these complex functional devices work to maintain homeostasis locally and throughout the body? In addition, melanocytes have also been shown to be localized in internal sites such as the inner ear, brain, and heart, locations not stimulated by sunlight. Thus, what can the observation of extracutaneous melanocytes tell us about the “secret identity” of melanocytes? While the answers to some of these intriguing questions remain to be discovered, here we summarize and weave a thread around available data to explore the established and potential roles of melanocytes in the biological communication of skin and systemic homeostasis, and elaborate on important open issues and propose ways forward.

Cutaneous‐immuno‐neuro‐endocrine (CINE) system: A complex enterprise transforming skin into a super organ

“…47 The immunomodulatory role of skin melanocytes has recently been described based on the display of inflammatory cytokine and neuromediator production leading to critical neuroimmune effects. 12,42,54 Fibroblasts maintain immune function in skin via expressing a variety of TLRs (TLR 1-9) and by releasing a wide variety of mediators such as AMPs, defensins, pro-inflammatory cytokines (INFγ, IL-6, TNFα, IL-10 and IL-12) and chemokines (CCL1,2 and 5, CXCL8,10 and CX3CL1). 55,56 Fibroblasts can exert local cutaneous pro-inflammatory cues through these cytokines and chemokines and via production of extracellular matrix proteins.…”

“…The immunomodulatory role of skin melanocytes has recently been described based on the display of inflammatory cytokine and neuromediator production leading to critical neuroimmune effects 12,42,54 …”

Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation

“…The physiological role of molecular elements of the HPT axis such as functional TSH and TRH receptors and biologically active TSH and TRH expressed on keratinocytes, melanocytes and dysplastic nevi is less clear [124]. UVR-damaged keratinocytes, however, are suspected to be involved in thyroid autoimmune diseases by triggering anti-TSH receptor antibodies [125], whereas TRH upregulation is proposedly involved in the malignant conversion of melanocytes into melanoma cells and their further proliferation and progression [126].…”

The skin‐brain connection and pleasant touch as supportive care for psychocutaneous disorders

“…The skin shares a common ectodermal origin with the brain, spinal cord, and peripheral nerves which helps explain the likely interactions between them and the similarity between specific skin cells and neurons. Furthermore, melanocytes also share signalling molecules, receptors and signalling pathways with cells of the nervous system 35–37 . Additionally, although the underlying pathophysiological mechanisms are not fully understood, the skin and brain are anatomically and functionally connected (skin‐brain axis) via a complex interplay between the skin and the nervous, endocrine and immune systems, with both central (systemic) and peripheral (local) pathways playing a role to modulate the response 15 .…”