Neuroendocrine activity of the melanocyte

Abstract

More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress. Examples of the above are catecholamines, serotonin, N-acetyl-serotonin, melatonin, proopiomelanocortin-derived adrenocorticotropic hormone, β-endorphin or melanocyte-stimulating hormone peptides, corticotropin releasing factor, related urocortins and corticosteroids including cortisol and corticosterone as well as their precursors. Furthermore, their production is not random, but hierarchical and follows the structures of classical neuroendocrine organizations such as hypothalamic-pituitary-adrenal axis, serotoninergic, melatoninergic and catecholaminergic systems. An example of an intrinsic but overlooked neuroendocrine activity is production and secretion of melanogenesis intermediates including L-DOPA or its derivatives that could enter circulation and act on distant sites. Such capabilities have defined melanocytes as neuroendocrine cells that not only coordinate cutaneous but also can affect a global homeostasis.

Melanocytes as sensory and regulatory cells of the epidermis: introduction into the concept

More than 15 years ago, it has been proposed for the first time that melanocytes are the sensory and regulatory cells with computing and amplifying capabilities, which detect and transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis (Fig. 1) (1). Specifically, melanocytes sense the environment directly via detection and decoding of the solar or thermal energy or indirectly by responding to biological or physicochemical signals generated in the local environment in response to noxious factors. The former (detection of electromagnetic energy) represents a rapid process of which specificity depends on the chromophores or their interactions with specific receptors or metabolic pathways (2).

Figure 1.

Melanocytes act as the sensory and regulatory cells of the skin with the computing capabilities. MC, melanocytes; KC, keratinocytes; LC, Langerhans cells; Ly, lymphocytes; Mast C, mast cells; MAC, macrophages; Fb, fibroblasts; EC, endothelial cells; DD, dermal dendritic cells; ⊙, melanosomes; →, direction of melanosomes movement/transfer,; =:, gap junctions; (): flow of ions and micromolecules. Reprinted with modifications from the J Theor Biol 1993: 164: 103–120, with permission from the Elsevier).

This concept is in agreement with a hypothesis that melanocytes are ‘neurons of the skin’ formulated by Aaron B. Lerner (Fig. 2) (G. Moellman, personal communication). At that time it also integrated novel theories formulated at Yale University by Pawelek on the mechanism of UV regulation of melanin pigmentation (3), and the theory of the melanin epidermal unit first proposed by Fitzpatrick and Breathnach (4) and then expanded by Nordlund (5). A ground-breaking was Pawelek’s hypothesis on the transduction of electromagnetic energy of solar radiation into chemical energy during the process of ultraviolet B (UVB)-induced melanogenesis connected with an increased melanocyte-stimulating hormone (MSH) receptor activity (3,6). His laboratory (3,6) clearly demonstrated that the effects of UV on pigmentation follow the mechanisms intrinsic to the skin for the orderly, regulated reception of UV signals that are then transduced to initiate the pigmentary cascade via signals involving both melanocytes and keratinocytes. According to this model, melanotropins and their receptors played a central role in this process (3). At the same time, Nordlund has proposed that melanocytes, keratinocytes and Langerhans cells interact closely within the epidermis forming the ‘epidermal tripod unit’, a hypothesis that was updated most recently by stating that the epidermal melanin unit should be labelled the KLM unit (5). These theories (3) as well novel concepts on hormone-like bioregulatory roles for precursors and intermediates of melanogenesis L-tyrosine and L-DOPA (7), secretory functions of melanocytes and their roles in skin and hair physiology and pathology (8,9) have helped to propose that melanocytes are sensory and regulatory cells of the epidermis (1), which set-up the background for defining a melanocyte as the unique neuroendocrine cell with multiple tasks.

Figure 2.

Picture of Aaron B Lerner, MD, PhD. Generously provided by Dr John Pawelek.

Melanogenic pathway as the regulator of skin homeostasis

It is unquestionable that the ability to produce melanin pigment plays a fundamental role in skin physiology and pathology and skin responsiveness to solar radiation (10–12). However, a role for the intermediates of the melanogenic pathway and its final products has not been clearly established, with exception of defining the role of melanin as the protector against solar radiation (1,10–13). In this context, a proposition, that precursors and intermediates of melanogenesis can act as regulators of local and systemic homeostasis (7,8), represented a mile stone in defining regulatory and neuroendocrine functions of the melanocyte (cf. 11). Specifically, it has been proposed that L-tyrosine and L-DOPA and products of their metabolic transformation can act as hormone-like or metabolic bioregulators in the skin or at systemic levels including modification of immune activity (1,7,11,14–20); hormone-like, but not metabolic, properties would require expression of specific receptors for L-tyrosine and L-DOPA and their metabolites (21,22). Furthermore, we were the first to propose that melanosomes serve as unique organelle/messengers, which regulate skin functions including its protective, bioregulatory and sensory capability, because of intrinsic melanin and melanosomal properties and the bioregulatory functions of melanogenic pathway (1,8). Part of this model has latter been adopted by other investigators (12,23,24).

Neuroendocrine functions of the melanocyte

Since then, this concept has been substantiated by significant experimental evidence showing that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, and that this production is stimulated by ultraviolet radiation, biological factors and other agents that act within the skin neuroendocrine system (reviewed in (14,25–29). Specifically, melanocytes produce corticotropin releasing factor (CRF) and related urocortin, and express corresponding functionally active CRF receptors types 1 and 2 (CRF1 and CRF2) (28–30). Signal transduction through the CRF receptors is coupled to different second messengers including cAMP, IP3 and Ca⁺² to most optimally regulate the phenotypic outcome such as melanogenesis, dendrite proliferation and regulation of cell proliferation (29,31,32) or NFκB activity (33) in a process that includes alternative splicing (29,34). Furthermore, melanocytes express proopiomelanocortin (POMC) that is processed to adrenocorticotropic hormone (ACTH), α-MSH and β-endorphin [(30,35,36) and reviewed in (11,26)], express MC1-R (37,38), MC2-R (39), MC-4 (40) and opioid receptors (41) and have corticosteroidogenic potential (42–44). Most recent data (40) have also confirmed our initial detection of cutaneous production of β-MSH by immunocytochemistry (45,46). Synthesis of steroid hormones in melanocytes can start from the cleavage of the side chain of cholesterol (42). Most importantly, the melanocyte CRF production and expression of CRF1 are regulated by UVB (29,34,47,48), CRF stimulates production of POMC with production of ACTH and α-MSH (43,49) and UVB-induced POMC and ACTH expression is dependent on the CRF production and CRF1 signal transduction (47). Thus, an evidence has been provided for the original hypothesis (50) that the production of the above molecules in pigment cells is hierarchical, and follows the algorithm of a classical neuroendocrine axis—hypothalamic-pituitary-adrenal axis (HPA) (25,29,43,51). This raised important questions on the evolution of the stress response system, which may have originated in the integument as well as on possible systemic implications of this process (14,26, 52–55).

Additional examples of melanocyte neuroendocrine activity are its ability to produce and secrete L-DOPA [a hormone-like bioregulator and a potential neurotransmitter (7,11,21)], its metabolic products (11), as well as production of catecholamines (56). The latter capability is significant as melanocytes express phenylalanine hydroxylase, tyrosine hydroxylase, express functional adrenergic receptors as well as have a capability for de novo synthesis/recycling and regulation of the pterin (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) (56–59). Importantly, we have demonstrated recently that normal and malignant melanocytes have the capability to transform L-tryptophan to serotonin, N-acetylserotonin and melatonin with its further metabolism (60–64). The serotoninergic/melatoninergic system is functional within the pigmentary system and melanocytes express serotonin and melatonin receptors (11,65,66). Lastly melanocytes can express elements of the hypothalamic-pituitary-thyroid axis (67) and elements of the cholinergic system (56).

Concluding remarks

The above capabilities clearly demonstrated that melanocytes could efficiently regulate local and perhaps systemic homeostasis. The latter may include direct release into circulation of the melanocyte signalling molecules (endocrine effect), or neurotransmitter-like effects by activation of specific receptors on cutaneous sensory nerve endings or by changing physicochemical environment surrounding such nerves (1,14,53,55). Accordingly, the cutaneous sensory nerves will signal the brain on changes in the epidermal environment or will relay to neuronal reflexes without brain involvement (1,14,55). These capabilities represent a dawn for the novel role of melanocytes, as neuroendocrine cells that translate environmental information into both local and systemic effects (1,14). In this context, when stressed, the skin pigmentary system can generate signals to produce rapid (neural) or slow (humoral) responses at the local or systemic levels (1,7,11). These responses are addressed at counteracting the environmental insults, and/or modulating optimally the homeostatic adaptation mechanisms. Thus, the skin melanocytic system may act as a sensor for external or internal disturbances to generate humoral or neural signals sent to local or distant coordinating centres (Fig. 1) as originally proposed by us (1,7,11,14).