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

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      Cells
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          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.

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          Most cited references214

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          The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.

          The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
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            Colloquium paper: human skin pigmentation as an adaptation to UV radiation.

            Human skin pigmentation is the product of two clines produced by natural selection to adjust levels of constitutive pigmentation to levels of UV radiation (UVR). One cline was generated by high UVR near the equator and led to the evolution of dark, photoprotective, eumelanin-rich pigmentation. The other was produced by the requirement for UVB photons to sustain cutaneous photosynthesis of vitamin D(3) in low-UVB environments, and resulted in the evolution of depigmented skin. As hominins dispersed outside of the tropics, they experienced different intensities and seasonal mixtures of UVA and UVB. Extreme UVA throughout the year and two equinoctial peaks of UVB prevail within the tropics. Under these conditions, the primary selective pressure was to protect folate by maintaining dark pigmentation. Photolysis of folate and its main serum form of 5-methylhydrofolate is caused by UVR and by reactive oxygen species generated by UVA. Competition for folate between the needs for cell division, DNA repair, and melanogenesis is severe under stressful, high-UVR conditions and is exacerbated by dietary insufficiency. Outside of tropical latitudes, UVB levels are generally low and peak only once during the year. The populations exhibiting maximally depigmented skin are those inhabiting environments with the lowest annual and summer peak levels of UVB. Development of facultative pigmentation (tanning) was important to populations settling between roughly 23 degrees and 46 degrees , where levels of UVB varied strongly according to season. Depigmented and tannable skin evolved numerous times in hominin evolution via independent genetic pathways under positive selection.
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              L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions.

              There is evidence that L-tyrosine and L-dihydroxyphenylalanine (L-DOPA), besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor-mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as regulate the melanocyte functions through the activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate-induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate an older theory proposing that receptors for amino acid-derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates. © 2011 John Wiley & Sons A/S.
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                Author and article information

                Contributors
                Journal
                CELLC6
                Cells
                Cells
                MDPI AG
                2073-4409
                July 2022
                June 30 2022
                : 11
                : 13
                : 2082
                Article
                10.3390/cells11132082
                35805166
                888698d8-2b91-48f9-a7f7-b9bd3a19ef87
                © 2022

                https://creativecommons.org/licenses/by/4.0/

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