Neuro–immuno–endocrinology of the skin: how environment regulates body homeostasis

Abstract

The skin, including the hypodermis, is the largest organ of the body. The epidermis, the uppermost layer, is in direct contact with the environment and is exposed to environmental stressors, including solar radiation and biological, chemical and physical factors. These environmental factors trigger local responses within the skin that modulate homeostasis on both the cutaneous and systemic levels. Using mediators in common with brain pathways, immune and neuroendocrine systems within the skin regulate these responses to activate various signal transduction pathways and influence the systemic endocrine and immune systems in a context-dependent manner. This skin neuro–immuno–endocrine system is compartmentalized through the formation of epidermal, dermal, hypodermal and adnexal regulatory units. These units can act separately or in concert to preserve skin integrity, allow for adaptation to a changing environment and prevent the development of pathological processes. Through activation of peripheral nerve endings, the release of neurotransmitters, hormones, neuropeptides, and cytokines and/or chemokines into the circulation, or by priming circulating and resident immune cells, this system affects central coordinating centres and global homeostasis, thus adjusting the body’s homeostasis and allostasis to optimally respond to the changing environment.

Introduction

Skin, integument, is the largest body organ, composed of three functionally different layers: epidermis, dermis and hypodermis. These three layers are of different embryonal origin (the epidermis and skin appendages are predominantly of ectodermal origin and the dermis and hypodermis are of mesenchymal origin) and differ in their constitutive and reactive functions depending on their anatomical location (scalp, face, torso, extremities and acral skin; Box 1), innervation and the nature of environmental factors^1–3 (Box 2). Skin structure, appearance and main functions vary across different species, determined by habitat, geographical and climatic environments (including latitude), and daily or nocturnal activity, with many functions being conserved across different animal taxa^4–6. The conserved functions of the skin include barrier function and, to different degrees, sensing the environment, protection from and reaction against pathogens, allergens, physical, chemical and biological factors, social communication and, in the case of animals, camouflage.

Box 1 |. Skin: an overview.

The skin forms a self-regulating, biologically and metabolically active barrier between external and internal environments². This barrier is supported by the skin immune system (composed of resident and circulating non-resident cells³¹), the pigmentary system¹⁴, the vasculature, and a neural network composed of adrenergic nerves, cholinergic nerves, and sensory unmyelinated and myelinated fibres^48,167. Histologically, skin comprises the epidermis, dermis and the inner layer hypodermis, which is composed predominantly of adipose and loose connective tissues. The dermis and hypodermis are penetrated by adnexal structures (appendages), including hair follicles and sebaceous, eccrine and apocrine glands that are connected to the epidermis. Embryologically, the epidermis and adnexal structures are predominantly of ectodermal origin, while dermal and hypodermal elements are of mesodermal origins⁴.

The structure, thickness and composition of the main elements and the function of the skin vary depending on their anatomic location. The cutaneous functions are affected by spinal sensory innervation of dermatomes (areas of skin supplied by afferent nerve fibres from spinal nerve ganglions) of the torso, extremities, posterior scalp and neck, and innervation of most of the scalp, face and upper anterior neck by branches of the trigeminal nerve¹. Examples of this anatomical variability are: the scalp containing numerous hair follicles producing terminal hair shafts¹⁹⁰; acral skin consisting of a thick, cornified granular layer with numerous sweat glands and sensory nerve endings but without pilosebaceous elements; facial skin with numerous vellus hair follicles and sebaceous glands; skin of the axilla and groin being rich in apocrine glands; and back skin having thick reticular dermis^1,4,5.

The epidermis — the outermost skin layer — predominantly develops from differentiating keratinocytes, which are cells of neuroectodermal origin, in the stratum basale. These keratinocytes give rise to the suprabasale, spinosum, granulosum and, finally, acellular stratum corneum, of which viable layers have immune–endocrine capabilities¹⁸. The epidermis contains cells of neural crest origin that exhibit neuro–endocrine–immune capabilities, including melanin-producing melanocytes and sensory Merkel cells, as well as circulating and resident immune cells of mesenchymal origin, including Langerhans cells that can also produce neurohormones^17,18. Sensory nerves also penetrate the epidermis up to the stratum corneum level^36,167,169.

The dermis, divided into the papillary dermis adjacent to the basement membrane and the reticular dermis, is composed of fibroblasts and fibrocytes, myofibroblasts, adipocytes, resident and circulating immune cells, and resident mast cells with neuro– endocrine–immune functions. With the hypodermis, these dermal layers contain hair follicles, sebaceous and eccrine glands, smooth muscle, nerves, and vascular and lymphatic structures^1,4.

The structural integrity of the skin and its functions are facilitated by the close connections between these compartments, the mutual signalling between them, and intercellular connections. These interactions are facilitated by the sensory neural network and circulating immune cells that, together with the vascular network, are crucial in transmitting skin signals to central and other peripheral organs.

Box 2 |. Environmental factors affecting the skin.

A major factor influencing the skin is solar radiation with its different wavelengths, including infrared (>700 nm), visible (400–700 nm) and ultraviolet (UV) (280–400 nm) light. The majority of the biological impact of light is exerted by UV light, both UVB (290–315 nm) and UVA (315–400 nm), which represent 3% of the radiation of the sun at zenith that reaches the Earth’s surface⁶. Each spectrum of solar radiation affects the skin via a different mechanism of action, with UVB acting through chromophores and UVA or visible light predominantly acting through reactive oxygen species with a lesser contribution from chromophores. Different wavelengths also penetrate the skin to different depths, with UVB reaching only papillary dermis, UVA reaching the reticular dermis and visible light penetrating deep into the hypodermis. Although the negative effects of UV are well established (including the induction of carcinogenesis, skin ageing and other pathologies¹), the positive effects of UV light on skin and systemic immune and global homeostasis, aside from vitamin D3 production^145,191, are gradually becoming appreciated, which involve different mechanisms of action such as activation of sensory nerves, stimulation of production of neuroendocrine and immune factors as well as production of vitamin D3, lumisterol and tachysterol^3,6. Cutaneous photoreceptors for visible light and UVA have been identified over the past 10 years^{177,178,192,193}, and the existence of UVB receptors has been proposed^3,43.

The biological factors affecting the skin encompass microorganisms (bacteria, fungi and viruses) contributing to skin infection or damage or to inflammatory responses via pathogen-associated molecular patterns binding to pattern-recognition receptors or other microbial molecules activating the cutaneous immune system, sensory nerve endings, or epithelial cells of the epidermis or adnexal structures^{19,21,38,123,194}. Different allergens, toxins or other biological factors of plant, microbial or animal origin can also induce allergic and inflammatory responses or lead to skin damage and/or necrosis. The positive effects of the skin microbiome on skin cutaneous homeostasis, similar to that described for the gastrointestinal tract²⁹, have been considered by several authors^{20,42,44,195,196}.

Chemical factors affecting the skin include nociceptive factors^40,171 and different classes of environmental pollutants acting directly on the epidermis, adnexa or dermis through receptor-dependent or receptor-independent mechanisms^10,11. Physical factors, in addition to touch and vibration detected by specialized sensory cells or nerves¹⁷⁰, include positive or negative thermal energy in the form of heat or cold. This thermal energy can be detected by sensory nerves or transient receptor potential channels expressed on skin cells^169,197. Finally, mechanical breaking of the skin structure induces the wound-healing process¹⁸¹, which also contains neuro–immuno–endocrine components^182–187.

Skin physiology, histology, cellular and structural composition (encompassing skin-resident cells (keratinocytes, melanocytes, fibroblasts and adipocytes), immune cells, nerves, muscles and vasculature) are detailed in Box 1. These aspects of skin physiology can vary substantially across different anatomical locations and species^2,4,7. The species difference is exemplified by differences between human and mouse skin, both in anatomy, cytoarchitecture, physiology and main functions, which in mice is dependent on the phase of the hair cycle^4,8,9, whereas in humans both epidermal and dermal compartments are affected by exposure to environmental factors^2,10,11, with different wavelengths of solar radiation being the predominant ones^6,12,13. Important intrinsic systems that affect not only skin functions but also systemic homeostasis and social communication are melanin pigmentary^13,14, adnexal (hair follicles, sebaceous, eccrine and apocrine glands)^15,16, immune¹² and local neuroendocrine^17,18 systems, which can act in concert to regulate local and systemic homeostasis. These systems can also communicate with the epidermal microbiome in a reciprocal fashion, affecting skin physiology or pathology^19–21.

The main environmental factors affecting the skin of diurnal animals and humans are outlined in Box 2. These encompass ultraviolet, visible and infrared light^3,6,22,23, biological factors (such as microorganisms, allergens and biological pollutants)^20,21, chemical factors, including pollutants, and wound-inducing trauma or physical stressors^2,10,11,24. In reaction to these factors, the skin can launch highly organized stress responses to counteract the damaging insults or restore and/or protect local homeostasis through the coordinated action of cutaneous neuroendocrine^17,18 and immune^12,21 systems, which act in coordination with central organs to affect systemic homeostasis. The skin also senses non-insulting environmental changes, including different wavelengths of solar light, humidity, temperature, pheromone-like signals and products of the commensal microbiome. These environmental changes are translated into signals that initiate homeostatic responses through an elaborate skin neuro–immuno–endocrine system that communicates with its counterparts at the central level^3,18.

In this Review, we present evidence for the concerted neuro– immuno–endocrine activities of the skin triggered by environmental changes that influence central and systemic homeostasis. The mechanistic background for such skin-based systems will be offered in the context of the evolution of stress responses and their regulation by the central neuro–immune axis^25–27.

Skin as an immune organ

The unique features of the skin as a peripheral immune system involve its direct contact with the external environment in contrast to other barrier organs¹, such as the gastrointestinal system, respiratory system and genitourinary systems, and are defined by the variety of immune responses from different cell types^28–30. Thus, in addition to cells of haematopoietic origin, the skin is composed of resident cells, such as keratinocytes and melanocytes, that sense antigens and react to environmental stressors through the release of cytokines or chemokines^1,12,31, affecting the local and systemic neuroendocrine system^3,18,32. Cells of the adnexa affect the local immune activity, with hair follicles having a privileged immune function^33,34. Furthermore, circulating immune cells (moving through or from the skin) differ in function as determined by their phenotype, anatomical location, and the presence or absence of different pathological conditions. For example, Langerhans cells, mast cells, dendritic cells and macrophages reside in the skin, while T cells, B cells, neutrophils, monocytes, eosinophils and basophils migrate from the circulation to specific skin locations after stressful insults or trauma. These components in concert protect the structural and functional integrity of the skin.

The innate and adaptive immune responses are both engaged in the skin. In adaptive immunity, antigen-presenting skin cells initiate T cell responses, leading to T helper 1 (T_H1), T_H2 and T_H17 responses. Langerhans and mast cells, keratinocytes and, to a certain degree, other skin-resident cells activate the adaptive immune system by presenting antigens to T cells and by producing a variety of immune mediators. The innate immune responses involve several innate immune cells that produce various cytokines, chemokines, antibacterial and anti-fungal peptides, prostaglandins, H₂O₂, reactive oxygen and nitrogen species, and other factors^1,12,31. Immunocompetent skin-resident cells (Supplementary Table 1) and circulating immune cells have the capability to produce neuroendocrine factors and express corresponding receptors^25,35. Sensory nerves detect biological signals and regulate local immune responses accordingly^36–39, while cytokines (such as IL-1, IL-6 and TNF) produced by skin cells can regulate the central neuroendocrine system^3,32,40. An important component of the skin immune system is the local microbiome that can not only modulate immune functions^21,41 but also the epidermal barrier^19,20 as well as cutaneous endocrine functions^42–44.

Skin as a neuro–immuno–endocrine organ

The original hypothesis that the skin is a neuroendocrine organ that secretes neuroendocrine and immune mediators to regulate local responses against environmental stress with systemic implications^17,45 has been validated and supported both experimentally and conceptually^{2,3,16,36,46–49}. We provide evidence in this section that this peripheral neuroendocrine system, in concert with its immune component and sensory nerve endings, can sense environmental signals and affect systemic homeostasis. These functions are achieved by the production of neuroendocrine factors by skin-resident cells and circulating immune cells, which is further complemented by sensory nerves releasing different neurotransmitters locally (Supplementary Table 1) and by the bidirectional communication between the local endocrine systems and the cutaneous microbiome^42,43 (Fig. 1).

Fig. 1 |. Skin homeostasis and allostasis are regulated by the local neuro–immuno–endocrine system in response to environmental factors.

The skin neuro–immuno–endocrine system is composed of epidermal, dermal, hypodermal and adnexal immune–endocrine units, the activities of which are coordinated by sensory nerves. The main cellular coordinating components are epidermal and follicular keratinocytes and melanocytes, Merkel cells, Langerhans cells and mast cells, with some contributions from fibroblasts, endothelial and immune cells, and sebocytes and adipocytes. Important coordinators are sensory nerves, which penetrate the epidermal and dermal structures and are in contact with their main cellular components. These immuno–endocrine units communicate among themselves through soluble factors released by skin cells or circulating immune cells or through rapid transmission by directly or indirectly activated sensory nerves in a bidirectional manner, allowing efficient communication among different compartments. The degree and specificity of the activation of immuno–endocrine units by environmental factors depends on their nature and penetration into different compartments of the skin as well as on neural intra-compartmental communications. Nerve endings up to the level of the stratum corneum can not only sense the environment but also release neuropeptides or neurotransmitters in response to stress to affect closely located cells. The cutaneous microbiome can also communicate with epidermal or adnexal immuno–endocrine units through the release of different soluble factors or neurotransmitters. UV, ultraviolet.

POMC-derived neuropeptides

The central role of the proopiomelanocortin (POMC) system in the regulation of body homeostasis is widely recognized. POMC is expressed in different brain regions, including the hypothalamus and the pituitary, as well as in immune cells and a variety of non-neuronal peripheral organs^45,50–53. Almost all skin cell types, including keratinocytes, melanocytes, fibroblasts, endothelial cells, sebocytes, adipocytes, Merkel cells, Langerhans cells, dendritic cells, mast cells, lymphocytes, monocytes and macrophages, and other haematopoietic cells, express POMC precursor protein and process it in a context-dependent and cell type-dependent manner to produce the corresponding regulatory peptides. These regulatory peptides include adrenocorticotropic hormone (ACTH) and its shortened forms (ACTH 1–13 and ACTH 1–17), melanocyte-stimulating hormones (αMSH, βMSH and γ1–3-MSH), β-lipoprotein and β-endorphin peptides, which are released into the extracellular environment^{14,16,18,45,47,54}.

POMC processing in the skin is like that in the brain and pituitary. Melanocytes, keratinocytes, fibroblasts, sebocytes and immune cells express functional PC1 and PC2 convertases and the regulatory protein 7B2. The coordinated activities of these proteins determine the nature of the final peptide and whether these are ACTH or β-lipoprotein or their processed products, αMSH, γMSH or βMSH and β-endorphin, respectively^{45,52,55–57}, resulting in both differential and overlapping downstream phenotypic effects^{45,55,56,58,59}. These neuropeptides, through interaction with the corresponding G protein-coupled receptor (GPCR) melanocortin receptor types 1–5 (MC1–MC5) or opioid receptors, can regulate the phenotype of resident and circulating cells via paracrine, autocrine or intracrine mechanisms^{45,55,56,58–60}. Specifically, they stimulate epidermal and follicular melanogenesis, strengthen the cutaneous epidermal barrier, have cytoprotective effects, modulate hair growth, and stimulate lipogenesis, sebum production and eccrine gland functions^{8,14,16,54–56,59}. In addition, these POMC-derived neuropeptides have immunosuppressive, antimicrobial, antifibrotic, radioprotective and thermoregulatory effects, influence nociception through action on corresponding receptors on nerve endings^{16,18,45,47,54–56,60–64}, and can affect the central energy control systems^50,52.

The best characterized of these effects are the stimulatory actions of αMSH on melanocytes or the inhibitory activity of αMSH on fibroblasts or immune cells via activation of, predominantly, MC1, with possible contribution of MC3 or MC4 activation⁵⁴. Actions on melanocytes are diverse and include stimulation of dendrite formation, melanogenesis, and cytoprotective mechanisms against oxidative stress, modulation of cell proliferation, inhibition of adhesion molecules, chemokine receptor expression and downregulation of nuclear factor-κB (NF-κB)^{14,45,54,55,59,65,66}. Anti-inflammatory, immunosuppressive and anti-pyretic functions of αMSH are widely recognized both in the skin and immune system^{45,52,54,55,64,67}. αMSH also inhibits proliferation and fibrogenic activity of fibroblasts as well as their pro-inflammatory functions^54,55,68. ACTH, the precursor of αMSH, aside from being a natural ligand of MC2, also acts on MC1 with similar but less pronounced phenotypic effects than those of αMSH, which include stimulation of melanogenesis, dendrite formation and modulation of cell proliferation as well as anti-inflammatory effects. Activation of MC1 (and, to some degree, of MC3 and MC4) by αMSH can be attenuated via receptor antagonism by agouti signalling protein (ASIP), agouti-related protein (AGRP) or β-defensin 3 (HBD3), depending on the species^69–71.

Additional mechanisms of action of POMC peptides within the skin include their activation of sensory nerve endings or the release of POMC peptides by skin cells, which can then enter the circulation with possible actions in peripheral organs such as immune organs or endocrine glands^{18,54,64,72–76}. The cutaneous production and local activity of POMC-derived αMSH, ACTH or β-endorphin is regulated by multiple stressors that include ultraviolet B (UVB) light, with lesser contribution from UVA^3,6,75,77,78, physical trauma including wounding, microbial macromolecules such as lipopolysaccharides and peptidoglycans, and pro-inflammatory cytokines such as IL-1, IL-6 and TNF^{18,39,61,79,80}. In addition, aberrant local POMC activity has been noted in pathological dermatoses^39,58 and during epidermal carcinogenesis or melanoma development and progression^79,81. These aberrant activities included increased expression of POMC and the processed peptides during melanoma progression or epidermal carcinogenesis, generating an immunosuppressive and pro-tumorigenic environment (discussed and reviewed in refs. 79,81). Once released into the circulation, POMC peptides can regulate systemic homeostasis through direct or indirect inhibition of immune activities, effects on endocrine glands or peripheral organs, or regulation of brain functions^2,79.

CRH and CRH-like peptides

Corticotropin-releasing hormone (CRH), a hypothalamic regulator of the pituitary–adrenal axis⁸², and the related urocortins are also expressed in the extrahypothalamic sites of the brain, endocrine organs, immune cells and several peripheral organs, where they regulate homeostatic functions via activation of CRH receptor type 1 (CRHR1) and CRHR2 (refs. 58,80,82–84). CRH and urocortins are produced by all skin-resident cells and several immune cell types in skin and can be released by sensory nerve endings^{58,80,85–87}. CRH and urocortins act on CRHR1 or CRHR2, coupled to either cAMP, IP3 or Ca²⁺ signalling, to regulate epidermal barrier function, pigmentary activity, hair follicle cycling, secretory sebaceous gland activity, and immune activities via paracrine, autocrine, neurocrine and intracrine mechanisms^{18,58,80,84,85,87–93}. While the cutaneous and immune phenotypic effects are predominantly mediated through activation of CRHR1α (CRH and urocortin 1) or CRHR2α and/or CRHR2β (CRH, urocortins 1–3), alternatively spliced forms of both receptors can alter the phenotypic functions of the primary isoforms^58,94. For example, membrane-bound alternatively spliced CRHR1 forms modify CRHR1α activity, while soluble receptor isoforms can negatively regulate the local availability of CRH and urocortin ligands through binding the ligand in the vicinity of the cells these peptides would act on⁵⁸. In addition, CRH-binding protein (CRHBP) is expressed in skin cells, adding a further level of complexity to this regulatory process⁵⁸. Importantly, there are substantial differences in CRH and/or urocortin signalling between human and rodent skin, with the latter predominantly dependent on the composition of urocortins and receptor isoforms, which are controlled by the phase of the hair cycle^58,95.

Production of CRH and urocortins by skin-resident cells and immune cells can be directly stimulated by cutaneous stressors, including UV radiation (predominantly UVB), by microbial antigens and physical trauma (including injury), or indirectly by pro-inflammatory cytokines induced by CRH and other stimulants^{2,3,72,77,80,92,96–98}. UVB and other environmental factors regulate the expression and composition of CRHR1 isoforms^58,94,99,100. Specifically, UVB stimulates expression of the main functional isoforms CRHR1α and CRHR1g; however, continuous exposure to UVB not only reduces the viability of keratinocytes but also increases the number of expressed CRHR1 isoforms, suggesting that receptor heterogeneity can improve the probability of keratinocyte survival^94,100. In addition, 12-O-tetradecanoylphorbol-13-acetate and factors that increase cAMP levels caused increased expression of CRHR1α and CRHR1g¹⁰⁰, while increased cell contact (confluent cultures) favoured expression of only one isoform, CRHR1α⁹⁴. Depending on the type and intensity of the cutaneous stressor, CRH and related urocortins can enter the systemic circulation and affect the central neuroendocrine system and functions of other organs^3,39,72,74. It is worthwhile to recognize that direct effects of CRH and urocortin in the periphery are pro-inflammatory^80,93, while indirect effects are anti-inflammatory. These anti-inflammatory indirect effects are mediated through stimulation of the production and/or release of POMC peptides and production and/or release of ACTH-stimulated cortisol or corticosterone along with activation of the hypothalamic–pituitary–adrenal (HPA) axis^52,53,58,82.

The cutaneous HPA axis

The HPA axis, at the central level, encompasses CRH production in the hypothalamus in response to stress. CRH is then delivered to the anterior pituitary, where it activates CRHR1α, stimulating the release of ACTH. In the adrenal cortex, ACTH activates MC2 to stimulate the release of cortisol, which counteracts stress and inhibits production of CRH and ACTH through a negative feedback mechanism. Pro-inflammatory cytokines, such as IL-1, IL-6 and TNF, can also stimulate production of CRH and ACTH both in the hypothalamus and pituitary^67,101. HPA axis-like functional organizations composed of combined CRH and POMC signalling also operate in peripheral organs, including skin^{18,30,47,102–104}, and to some degree in the immune system^2,105.

In this context, the cutaneous HPA axis is activated directly by environmental stressors and forms complex regulatory networks involving CRH and/or urocortins, CRHR1, POMC-derived ACTH and locally produced corticosteroids. All of these factors interact with cutaneous pro-inflammatory cytokines and are in close spatial proximity to each other. This contrasts with the central HPA axis, which is anatomically separated between distinct organs, that is, the brain, pituitary and adrenals^2,3,18. Therefore, these interactions in the skin can self-organize into truncated circuitries composed of selected or full elements of the cutaneous HPA axis, including cytokines (IL-6, IL-6 and TNF), with phenotypic outcomes that include immunosuppression, stimulation of melanin pigmentation, stimulation of hair growth or secretory activity of sebaceous glands, which are discussed in depth in refs. 58,79. Although it has been hypothesized that the order of factors in the cutaneous HPA axis induced by various external stressors follows the classic organization of the central HPA axis (CRH and/or urocortin to CRHR1 to POMC to ACTH to cortisol or corticosterone to phenotype), several probable departures from this order have been proposed^18,58 (Fig. 2).

Fig. 2 |. Cutaneous equivalents of the central HPA axis.

The central hypothalamic–pituitary–adrenal (HPA) axis is composed of corticotropin-releasing hormone (CRH), CRH receptor type 1 (CRHR1) and proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH), which acts on the MC2 receptor to stimulate cortisol and corticosterone secretion and production. The HPA axis is activated by stress or pro-inflammatory cytokines. In addition to this central HPA axis, truncated regulatory pathways composed of selected elements of the HPA axis within the skin (the cutaneous HPA axis) have been envisioned. These pathways include the stimulation of CRH and/or urocortin by stress or cytokines, which activates CRHR1 and/or CRHR2 and leads to increased expression of POMC. POMC is then processed to ACTH and β-lipotropin (βLPH), which are, respectively, processed to α-melanocyte-stimulating hormone (αMSH) and β-endorphin without stimulation of the glucocorticoids (GCs) cortisol and/or corticosterone by ACTH. Shorter pathways represent direct stimulation of POMC expression by stress or cytokines. POMC is then processed to ACTH and βLPH, which are, respectively, processed to αMSH and β-endorphin. ACTH can then either stimulate or fail to stimulate the production of cortisol and/or corticosterone. Other shorter pathways include the stimulation of CRH and/or urocortin, which leads to pro-inflammatory and cytoprotective responses via activation of CRHR1 or CRHR2. Finally, direct stimulation of cortisol and/or corticosterone production by cytokines is envisioned. In the pathways described above, cortisol and/or corticosterone would inhibit the upper regulators, including CHR and/or urocortins, POMC-derived peptides, and cytokines, and attenuate the activities of corresponding receptors. Lack of cortisol and/or corticosterone production could lead to skin pathology.

The direct stimulation of cytokine production by CRH and urocortin has pro-inflammatory effects and stimulates cytokine production and NF-κB activity in keratinocytes^97,106,107 (reviewed in ref. 58). Inhibition of such pro-inflammatory activity by POMC peptides stimulated by CRH has also been envisioned^{58,91,102–104,108}. In the scenarios described in Fig. 2, cortisol and/or corticosterone would inhibit the upper regulatory axes of these pathways, including CHR and/or urocortins, POMC peptides and cytokines, and would attenuate the activity of their corresponding receptors. On the other hand, production of CRH and POMC peptides would be self-amplified via CRHR1 and/or CRHR2 and MC1 through activation of cAMP or Ca²⁺ signalling, resulting in increased cAMP or Ca²⁺ levels, which are well-recognized regulators of CRH or POMC peptide production^58,91,96. Such interactions would be defined by local histoarchitecture, cell lineage and the specific nature of the stressor. In pathological conditions (for example, dermatoses, skin ageing, pigmentary and hyperproliferative disorders, or oncogenesis and tumour progression), the organizational structures of the cutaneous HPA axis would be impaired, leading to intracrine, autocrine and paracrine mechanisms permitting pathology to develop or self-amplify. Such processes can potentially affect local and central circadian rhythms as levels of ACTH and corticosterone and/or cortisol fluctuate along the circadian rhythm⁷⁹.

In line with these considerations, it has been proposed that HPA axis organization, with attendant immune signalling, developed first in the integument (skin) to promote optimal responses against pathogens and other physical or chemical stressors and was then adapted and perfected by the central neuroendocrine system communicating with the immune system²⁷.

Brain, pituitary hormones, and other hormones and/or neuropeptides

Many hypothalamic and pituitary hormones are produced by skin-resident cells and immune cells that reside in or migrate into the skin. In the cutaneous context, these hormones regulate skin barrier, adnexal, dermal, hypodermal and immune functions through interactions with their corresponding membrane-bound receptors (Supplementary Table 1). These functions include the production of hypothalamic thyroid-releasing hormone (TRH), which can have direct and indirect modulatory effects on epidermal and follicular keratinocyte proliferation and differentiation, hair follicle cycling, and the wound-healing process. In addition, TRH has anti-apoptotic effects, regulates mitochondrial functions and stimulates melanogenesis^{2,47,71,109–113}. The indirect effects of TRH follow an organization of the local hypothalamic–pituitary–thyroid axis that includes stimulation of cutaneous production of thyroid-stimulating hormone, resulting in an increase in thyroxine and triiodothyronine that can subsequently affect skin physiology^{2,47,109–112}.

Oxytocin is a hormone produced centrally by the hypothalamus and released in the posterior pituitary. Oxytocin is also produced by keratinocytes and can regulate epidermal functions and immune activities through interaction with the GPCR oxytocin receptor^114,115. Among the pituitary hormones that deserve attention is prolactin, which is produced locally in the skin, where it regulates epidermal, hair follicle and immune functions through interaction with the GPCR prolactin receptor⁴⁷. In addition, growth hormone (GH), which profoundly affects skin physiology and pathology by action on keratinocytes, fibroblasts, immune cells, hair follicles and sebaceous glands, can be produced by dermal cells and immune cells^47,116–119. GH-releasing hormone is also expressed in hair follicle keratinocytes and dermal papilla cells, with co-expression of corresponding receptors to regulate hair follicle functions¹²⁰. GH action in the skin involves direct effects through activation of the GH receptor (a GPCR) or indirect effects through stimulation of dermal production of IGF1 (ref. 47) or additional mechanisms as has been described in hair follicles¹²⁰. Somatostatin, a neuropeptide produced in the hypothalamus and gastrointestinal tract, is also expressed in skin, where it can regulate hair follicle cycling and help to maintain the hair follicle as an immune-privileged site. In addition, somatostatin contributes to epidermal barrier function, wound healing, and dermal fibroblast and endothelial cell functions and can exhibit immunoregulatory properties^18,47,121. Pituitary adenylate cyclase-activating polypeptide, originally purified from the hypothalamic extract, in addition to being produced in the central nervous system, is also produced in the immune system and peripheral organs, including skin^122,123. It has a role in skin inflammatory responses, vascular functions and antimicrobial activities at the systemic level. Neuropeptide Y, mainly produced in the brain and autonomic nervous system, is also produced by resident and immune skin cells with local regulatory functions (reviewed in 2022 (ref. 124)).

The cutaneous opioid system, along with the previously mentioned POMC-derived endorphins, encompasses locally produced or released enkephalins and dynorphins (products of, respectively, the precursors proenkephalin or prodynorphin) or endomorphins as well as the corresponding GPCR opioid receptors (μ, κ and δ) and nociceptin receptors (NOP or OPRL1)^2,61,125,126. These opioid peptides, in addition to being released from sensory nerve endings in different cutaneous compartments, are produced by the main epidermal, follicular and dermal cells (keratinocytes, melanocytes, sebocytes and fibroblasts) and by skin-resident and circulating immune cells. The expression of opioid receptors on cutaneous non-immune (epidermal and follicular keratinocytes and melanocytes, sebocytes, fibroblasts, adipocytes, endothelial cells and smooth muscle cells) and immune cells as well as on sensory nerve endings forms a local opioid neuro–immuno–endocrine system that can regulate skin homeostasis. This system can affect the central nervous and systemic immune systems through the release of opioids into the circulation or through activation of opioid receptors expressed on sensory neurons that project to the brain or other organs, triggering reflex mechanisms^{2,18,40,61,125–128}.

Another group of neuropeptides that, in addition to their origin and/or release from cutaneous sensory nerve endings, are also produced by immune and skin-resident cells are calcitonin gene-related peptide, neurotensin, parathyroid hormone (PTH), PTH-related protein, vasoactive intestinal peptide, pancreatic polypeptide Y and tachykinins such as substance P and neurokinin A. The local production of these neuropeptides and their role in modulating functions of different skin compartments (epidermal, dermal and adnexal), including immune cells, via transmission of the signals to the brain after activation of the corresponding sensory nerve endings, have been the subject of more than 25 years of investigation^{17,18,38,47,80,122,128}. Similarly, the role of locally produced neurotrophins, including neuron growth factor, in skin physiology and pathology has been investigated for more than 30 years^17,129,130. Also worthy of mention is the cutaneous leptin system, encompassing locally produced leptin and expression of the leptin receptor¹³¹. Interestingly, UV radiation can inhibit leptin release from the skin¹³². Given that leptin is widely recognized to have immunoregulatory properties and interactions with POMC and/or CRH signalling, it is possible that the cutaneous leptin system could have a direct or indirect role in the regulation of local physiological functions through inhibition of POMC or CRH signalling. Alternatively, the cutaneous leptin system might affect body homeostasis and central activity when released from the dermis or hypodermis into the circulation.

Steroidogenesis in the skin

Human skin compartments, including the epidermis, pilosebaceous units, dermis and hypodermis (subcutaneous adipose and connective tissue), are recognized as extra-adrenal and extra-gonadal steroidogenic tissues capable of locally producing corticosteroids and sex hormones directly from cholesterol. This synthesis starts with cleavage of cholesterol by CYP11A1 to pregnenolone, the precursor to all steroid hormones, or from their precursors delivered from the circulation (dehydroepiandrosterone and progesterone)^30,133–136. Production of glucocorticoids in epidermal and dermal skin cells has been well documented over the past two decades, as has their role in skin pathophysiology^{77,102–104,135–139}. CYP11A1, the rate-limiting enzyme of steroidogenesis, is expressed in activated immune cells and drives the production of glucocorticoids, oestrogens and androgens along with their precursors^35,105,140. The local production and metabolism of steroids, including glucocorticoids, oestrogens and androgens, can not only regulate functions of peripheral organs and local and systemic immune activities but also have a role in the communication of the skin with different organs under physiological and pathological conditions^{30,79,105,133,134,141}.

Production of glucocorticoids in the skin can be stimulated by local and systemic stressors, including UVB, physical trauma (including wounding), changes in humidity, microbial factors and cutaneous pathological conditions (such as dermatoses, cancer and melanoma) through mechanisms that involve actions of CRH, ACTH, cytokines and factors that raise intracellular cAMP levels^{3,77,102,103,137–139}. Importantly, UVB, in addition to stimulating the cutaneous HPA axis, also stimulates systemic glucocorticoid release and/or production in the adrenals through activation of the central HPA axis^6,72,74 with the pituitary having a critical role in this process. However, the rapid responses to UVB (30–90 min after exposure of back skin to UVB) do not involve the pituitary and seem to involve neural transmission from sensory neurons in the skin to the spleen⁷².

Worth mentioning is the pathway initiated by enzymatic cleavage of the side chain of 7-dehydrocholesterol by CYP11A1 to produce 7-dehydropregnenolone that is further converted into 7Δ-steroids, which exhibit biological activity in immune and skin cells, as has been extensively described over the past 20 years^142,143. This system also operates in the skin, in which 7Δ-steroids, after exposure to UVB, are photochemically converted to vitamin D-like, lumisterol-like and tachysterol-like compounds that have biological activity on skin cells, including antiproliferative, pro-differentiation, antifibrotic, photo-protective, anticancer and immunomodulatory effects^143,144. These studies identified a new family of steroidal and secosteroidal compounds that are produced (or potentially produced) in the skin. However, most of the systemic and/or immunoregulatory functions of these compounds remain to be investigated and their corresponding nuclear receptors remain to be identified. We also note that 7-dehydropregnenolone has been identified in honey and insects⁴³, opening new areas for investigation, as CYP11A1 is expressed only in vertebrates.

Vitamin D3 and its derivatives

More than 95% of systemic vitamin D3 is derived from the skin through UVB-induced phototransformation of 7-dehydrocholesterol to vitamin D3, lumisterol3, and tachysterol3 and is dependent on total energy exposure and temperature^145,146 (Box 3). In the canonical pathway, vitamin D3 is activated through sequential hydroxylation at C25 and at C1α to produce biologically active 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3). CYP27B1 (also known as C1α-hydroxylase), the main regulator of local and systemic levels of 1,25(OH)₂D3, is expressed in the skin, kidneys and various other organs and immune cells. 1,25(OH)₂D3 exerts its biological activity through interaction with the vitamin D receptor^145,146, is an important regulator of skin barrier and adnexal functions, and can regulate local and systemic immune system through inhibition of adaptive immunity and stimulation of innate immunity¹⁴⁶.

Box 3 |. Vitamin D, lumisterol and tachysterol as prohormones.

The absorption of ultraviolet B (UVB) energy by the unsaturated B-ring of 7-dehydrocholesterol in the skin generates pre-vitamin D3, which, being thermodynamically unstable, undergoes isomerization to either vitamin D3 or, under high doses of UVB, to tachysterol or lumisterol^145,146. Although the role of vitamin D3 as a pro-hormone is well established^145,146, a similar function for lumisterol and tachysterol has been proposed only in the past few years^143,144,147.

To exert its biological activity, vitamin D3 is activated by sequential hydroxylations either locally in the skin or at the systemic level^145,146. In the traditional pathway, vitamin D3 is hydroxylated at C25 by CYP2R1 or CYP27A1 to 25-hydroxyvitamin D3, which is then hydroxylated at C1α by CYP27B1 to generate 1α,25-dihydroxyvitamin D3 (1,25(OH)₂D3). The inactivation of 1,25(OH)₂D3 is mediated by CYP24A1, which shortens its side chain resulting in the production of calcitroic acid^145,146.

Over the past 20 years, an alternative pathway of vitamin D activation has been discovered, which starts with hydroxylation of the vitamin D side chain by the steroidogenic enzyme CYP11A1 (ref. 144). The main product of vitamin D, 20(OH)D3, or other monohydroxy derivatives, can be hydroxylated by CYP11A1 to dihydroxy products and trihydroxy products, which can also be modified by CYP27A1, CYP24A1, CYP2R1, CYP3A4 and/or CYP27B1; except for 17,20,23(OH)₃D3. At least 18 hydroxy metabolites of vitamin D3 have been identified^143,144. In addition, lumisterol and tachysterol can be hydroxylated by CYP11A1 and CYP27A1 to produce monohydroxy metabolites and dihydroxy metabolites, with chemical structures established for five lumisterol and two tachysterol products^143,144,147. Many of these metabolites are detectable in human skin or skin cells, serum, placenta, and bovine adrenals^{143,144,147,198}.

1,25(OH)₂D3, in addition to regulating calcium homeostasis, has several pleiotropic effects that affect almost all physiological and developmental functions in the body, exerting antiproliferative, anticancerogenic, radioprotective, anti-oxidative, anti-inflammatory, antifibrotic and antimicrobial effects^145,146. Its phenotypic activities are predominantly mediated through interaction with the vitamin D receptor. Similarly, CYP11A1-derived vitamin D3 hydroxy metabolites exert similar biological effects to classical 1,25(OH)₂D3, as demonstrated in in vitro, ex vivo and in vivo models^143,144. The compounds without C1α(OH) act as ligands on liver X receptor, peroxisome proliferator-activated receptor-γ (PPARγ) and aryl hydrocarbon receptor, and as inverse agonists on retinoid-related orphan receptor-α (RORα) and RORγ. However, the compounds with C1α(OH) show selectivity for the vitamin D receptor. Lumisterol and tachysterol are also biologically active by acting on the above-mentioned receptors with selectivity defined by their chemical structure^143,144,147.

Thus, UVB-exposed skin can generate a large number of biologically active sterol and secosteroidal photoproducts that regulate local and global homeostasis after entry into the circulation, explaining many of the beneficial effects of UVB that cannot be achieved by oral vitamin D delivery.

New alternative pathways of vitamin D3 activation by CYP11A1 have been discovered^143,144. These alternative pathways lead to the production of hydroxyderivatives, of which 18 have been discovered thus far^143,144 (Box 3). Furthermore, lumisterol3 and tachysterol3 (previously considered inactive photoproducts of prolonged exposure to UVB) can be enzymatically activated to biologically active derivatives by either CYP11A1 or CYP27A1 (refs. 143,147). Many of these compounds are detectable not only in the human body^144,147 but also in insects and honey, indicating their wide distribution in nature despite functions traditionally reserved for vertebrates⁴³. In the mammalian system, vitamin D3, lumisterol3 and, potentially, tachysterol3 derivatives can regulate skin functions and have immunomodulatory effects similar to those of 1,25(OH)₂D3 by acting on alternative nuclear receptors, such as retinoid-related orphan receptor-γ (RORγ) and/or RORα, aryl hydrocarbon receptor (AhR), liver X receptor-α (LXRα) and/or LXRβ, peroxisome proliferator-activated receptor-γ (PPARγ), and perhaps others, in addition to the vitamin D receptor^143,147. These compounds can serve as endocrine cutaneous messengers of the sun, regulating systemic homeostasis in a manner defined by the nature of the nuclear receptors upon which they act.

Biogenic amines and melatonin

Skin and its immune system are recognized targets for biogenic amines, melatonin and their metabolites. The production of hista-mine by skin cells and its local effects are well known^1,2,80; therefore, we will focus our analysis on local serotoninergic, melatoninergic and catecholaminergic systems.

Human and rodent skin can transform l-tryptophan to serotonin, which is further metabolized to N-acetylserotonin and finally to melatonin^148–152. All skin-resident cells have this capability and the property is also shared by the majority of immune cells¹⁵³. Melatonin can be further metabolized through indolic or kynuric pathways to biologically active metabolites that can also be produced in the epidermis through the non-enzymatic action of UV radiation^154,155. Regulation and protection of skin homeostasis by melatonin and its metabolites are mediated via interaction with membrane-bound serotonin receptors^2,80,156, melatonin MT1 and MT2 receptors¹⁵⁷, and the AhR or PPARγ^152,158. Receptor-independent mechanisms of melatonin action also have a role in cytoprotective responses. It must be noted that serotonin and melatonin are also produced by bacteria and many unicellular organisms^43,153,159; therefore, the cutaneous microbiome can potentially contribute to skin serotoninergic and melatoninergic systems, as has been reported for the gastrointestinal system^153,159.

It is well established that skin-resident cells and immune cells have the capability to produce catecholamines and l-dihydrophenylalanine (l-DOPA)^2,48,160,161. Although their role in the regulation of the functions of different cutaneous compartments and the immune system has been established^{2,48,160–163}, their regulation of the cutaneous microbiome was also proposed in a 2020 study⁴². l-DOPA, products of its auto-oxidation, products of catecholamine auto-oxidation and intermediates of melanogenesis all have powerful receptor-independent immunosuppressive effects (reviewed in refs. 161,162). As adrenaline is a recognized regulator of melatonin release and synthesis through stimulation of serotonin acetylation, a role for the cutaneous catecholaminergic system⁴⁸ in the regulation of local serotonergic and/or melatonergic systems has been suggested^2,151.

Cutaneous cholinergic and cannabinoid systems

Human skin expresses a local, non-neuronal cholinergic system encompassing the production of acetylcholine by keratinocytes, fibroblasts, endothelial cells and circulating immune cells^48,49,164. This system is composed of choline, locally produced acetylcholine, and their corresponding muscarinic and nicotinic receptors expressed by skin-resident and immune cells. This cholinergic system modulates epidermal, sweat gland, hair follicle and other adnexal functions as well as the local vascular system and immune responses through autocrine, paracrine and endocrine mechanisms of action^49,164,165. It also interacts with the local adrenergic system through action on corresponding nicotinic and muscarinic receptors on skin cells that can produce catecholamines or are targets for catecholamine phenotypic activity⁴⁸. These cutaneous non-neuronal functions are in addition to the cholinergic activity of the local cutaneous nerves.

The cutaneous endocannabinoid system is well recognized^2,166. It is composed of cutaneously produced endocannabinoids that act on corresponding endocannabinoid receptors in autocrine, paracrine and neurocrine fashions¹⁶⁶. This system affects diverse local physiopatho-logical processes and communicates with the skin’s local neurosensory system¹⁶⁶ with the potential to transmit signals to the brain through ascending nerves after activation of corresponding receptors on nerve endings; this has potential modulatory effects on learning and memory, emotions, control of pain, eating and sleep behaviour.

Role of the cutaneous neural network in the regulation of skin functions

The cutaneous neural system is composed of networks of somatosensory and autonomic nerves terminating in each skin layer, with sensory nerve endings even penetrating the non-viable stratum corneum of the epidermis in addition to penetration of the dermal, hypodermal and adnexal structures^{36,40,122,167–170}. The concerted activity of these neurons in reaction to environmental factors and their interactions with the skin immune, endocrine and microbiome systems can regulate the physiological functions of the skin or can counteract or contribute to skin pathology such as inflammatory and hyperproliferative disorders, skin ageing, and skin tumours (extensively described in several reviews^{3,18,36,39,40,44,61,79,122,167–169,171,172}) (Box 2). Briefly, depending on the direct environmental stimuli (for example, different wavelengths of solar radiation, temperature, wound response, microbial or chemical insults, or changes in humidity) or through their indirect effects via local production of stress neurohormones or cytokines, sensory nerve endings can be activated. They can release neurotransmitters, various neuropeptides, neurotrophins, neurohormones or even gases (nitric oxide or carbon monoxide) that act on effector skin and immune cells as well as on adnexal structures, smooth muscle, cutaneous vasculature and adipose tissue. After activation, cutaneous sensory nerve fibres transmit these signals through antidromic signalling (efferently, releasing neurotransmitters on the effector skin cells) to achieve optimal homeostatic communication between distal cutaneous compartments or through orthodromic signalling (afferently to the spinal cord and brain) to regulate global homeostasis via endocrine glands and/or immune organs or to directly affect other internal organs¹⁷ (Fig. 1). These mechanisms are consistent with newly developing concepts of global neuroimmune regulation involving the central nervous system and its bidirectional communication with the immune system^{25,36,173,174}.

Environmental regulation of the skin neuro–immuno–endocrine system

Diverse environmental factors affect skin homeostasis and allostasis in a manner defined by the nature of environmental factors or disturbances of the environment and involving activation of local neuro–immuno–endocrine systems (Fig. 1 and Box 2). These environmental factors include the action of different wavelengths of solar radiation, such as UV radiation and visible and infrared light, which induce physicochemical changes in the skin. Solar light induces changes in local chemical composition (ionic composition, ionic strength, reactive oxygen or nitrogen species) or in the structure of extracellular organic molecules or organic molecules released from damaged cells. These molecules are then detected by sensory nerves and by the environmentally induced release of mediators from skin cells or priming immune cells and act as cellular ‘photo-messengers’ to regulate local and systemic homeostasis and/or allostasis^{3,6,12,132,175,176} (Figs. 1 and 3, Boxes 2 and 3, and Supplementary Table 1). UV radiation and visible light can be sensed by cutaneous photoreceptors^{3,6,22,175,177,178}. In addition, variations in the composition of UV radiation depending on the elevation of the sun and differences in atmospheric absorption will have allostatic effects on the skin. For example, the appearance and gradual increase of the UVB fraction in solar radiation reaching the Earth throughout the day will be sensed by 7Δ-dienes, leading to their phototransformation to vitamin D, lumisterol and tachysterol^3,43,143,179. Active forms of vitamin D, lumisterol and tachysterol all induce the assembly of protective mechanisms in anticipation of incoming radiation or oxidative damage. Similarly, UV radiation can affect cutaneous allostasis through stimulation of the pigmentary system^3,14,18, preparing the skin for incoming increased UV radiation doses with potential to induce damage in the skin. Both of these systems are examples of cutaneous allostasis, that is, preparation of the skin for incoming damages and environmental changes.

Fig. 3 |. Skin can regulate global body homeostasis and allostasis.

Regulation by the skin (red arrows) is indirect and secondary to the activation of the brain or spinal cord, endocrine glands (yellow arrows), systemic immune system (teal arrows) and distant internal organs (orange arrows). Soluble factors and immune cells from the skin affect the activities of these coordinating centres, the immune system and various internal organs in a reciprocal fashion, following a hierarchical structure involving inter-organ communication via the circulatory system. The signals from the skin to the central nervous system (CNS) or immune cells are also transmitted by sensory nerves (light blue arrows) that sense environmentally induced disturbances in the cutaneous ecosystem. The retrograde signals can also be sent from activated immune cells to the skin or be directly transmitted to the brain. After receiving and computing all the afferent signals sent from the skin, or other organs affected by skin factors, the brain makes decisions about how to regulate skin and other organs through the autonomic system (dark blue arrows). These CNS-dependent and CNS-independent connections affect global homeostasis and allostasis.

Various pollutants can affect skin homeostasis through action on cutaneous neuro–immuno–endocrine elements, including AhR signalling, as discussed in several reviews from the past 2 years^10,11,44 (Fig. 1). The extreme form of these insults are represented by warfare vesicants¹⁸⁰. In addition, the wound-healing process in response to trauma also involves neuro–immuno–endocrine components as discussed in previous publications^181–187. Finally, biological insults, including allergens, toxins or microorganisms, are sensed by different components of the local neuro–immuno–endocrine system, which can launch local and systemic homeostatic responses as discussed in Box 2 and in papers from the past two decades^{21,25,36,42,44,173,174}. The cutaneous microbiome can also have positive effects on the skin and, indirectly, on global homeostasis via the production of regulatory factors that act on the epidermis or adnexal structures, in a mechanistically similar manner to that described in the gastrointestinal system^{20,21,42,153,159,188} (Fig. 1).

Communication between the skin, brain, and central endocrine and immune systems

The skin communicates with the brain, endocrine and immune systems, and internal organs in a reciprocal and organized fashion (Fig. 3). This communication, and the resulting modulation of body homeostasis and allostasis, is context dependent and defined by the nature of the signals generated in the skin and modes of their transmission, for example, through the circulation or sensory nerves (Fig. 3). Factors transmitted via the circulation include hormones, cytokines, chemokines or hormone precursors, of which vitamin D, lumisterol and tachysterol and their derivatives are examples^3,143,144 (Supplementary Table 1). The sensory neurons provide rapid routes of sending information from the skin to the brain or other central coordinating organs. Both of these mechanisms exemplify the role of the skin in systemic allostasis, preparing the body for seasonal changes marked by the degree of sun exposure. Thus, environmental stress, stimuli or changes in the local environment will impact the nature of the cutaneous neuro–immuno–endocrine messengers (Fig. 1 and Boxes 2 and 3). These messengers also include locally primed circulating immune cells acting on the systemic levels in a neuro–immuno–endocrine fashion.

Conclusions

The skin, as a neuro–immuno–endocrine organ, can directly or indirectly (through central neuro–immuno–endocrine systems) regulate both local and global homeostasis and allostasis in a manner defined by the environment and its capability to generate diverse signals in a context-dependent fashion (Figs. 1 and 3). The discussed environmental–skin connections place this organ as a central player in allostasis¹⁸⁹, a mechanism by which the body predicts and adjusts physiological mechanisms in relation to a changing environment. The allostatic and homeostatic functions of the skin represent the evolutionary conservation of a primordial role of the integument, in which the majority of homeostatic responses to the environment would have developed²⁷.

The clinical implications of the neuro–immuno–endocrinology of the skin in dermatology have been discussed^18,47,49. These implications can be further extended into systemic diseases such as autoimmune (for example, rheumatoid arthritis, ulcerative colitis, Crohn’s disease and multiple sclerosis), neurodegenerative, cardiovascular, and mood disorders, metabolic syndrome, addiction^3,6, or internal cancers^79,81, with potential beneficial effects of different wavelengths of solar radiation on these processes. The positive effects of solar radiation would provide an additional credence for phototherapeutic approaches including UV therapy in the treatment of systemic disorders.

Supplementary Material

Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41574-025-01107-x.

Key points.

• The skin separates the internal milieu from the environment and is composed of the predominantly neuroectoderm-derived epidermis, an adjacent, predominantly mesoderm-derived dermis with hypodermis largely composed of fibroadipose tissue.

• Skin is exposed to a variety of environmental signals, including solar radiation of different wavelengths, biological, physical and chemical insults, and pollutants.

• Locally produced mediators, including classic pituitary and hypothalamic hormones, neuropeptides, cytokines and chemokines, biogenic amines, serotonin, melatonin, cannabinoids, steroids, and secosteroids, supported by a cutaneous neural network, regulate protective responses against environmental insults.

• The skin neuro–immuno–endocrine system communicates with the local microbiome, neural, endocrine and immune systems through the production of soluble factors, priming circulating immune cells or neural transmission.

• Environmental changes are detected and analysed locally and are transmitted to the central coordinating centres to regulate local and central homeostasis.

• Selective activation of the skin neuro–immuno–endocrine system can have a role in protection against skin pathologies and in the prevention and treatment of systemic disorders, including autoimmune, neurodegenerative and cardiovascular disorders or carcinogenesis.