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The Neuro-Immuno-Cutaneous-Endocrine Network: Relationship of Mind and Skin
Richard L. O'Sullivan, MD;
Graeme Lipper, MD;
Ethan A. Lerner, MD, PhD
Arch Dermatol. 1998;134:1431-1435.
ABSTRACT
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Skin does more than present one's "face" to the world; it plays a vital role in the maintenance of physical and mental health. As our most ancient interface, skin retains the ability to respond to both endogenous and exogenous stimuli, sensing and integrating environmental cues while transmitting intrinsic conditions to the outside world. As such, it has long been a target for the application of both medical and nonmedical therapies of healthy and diseased states. Our understanding of how the skin and topical therapies affect health is in its infancy. Conversely, we know little of how our internal systems affect our skin. By exploring an elaborate web of neuro-immuno-cutaneous-endocrine (NICE) phenomena, we seek to shed light on the generally acknowledged, but inadequately defined, relationship between mental and physical health. We use skin as our window, noting some of the biological mediators linking nervous, immune, cutaneous, and endocrine functions. It is likely that these mediators are important in homeostasis, and that they affect several dermatologic and psychiatric conditions.
INTRODUCTION
We are always slow in admitting great changes of which we do not see the steps.—Charles Darwin1
A view of integrated mind, brain, and body connections in wellness and disease has been appreciated for centuries. Yet the conventional medical community still trivializes this complex set of relationships, and has alienated many patients. Notably, US patients visited alternative practitioners 425 million times in 1990—40 million more times than they visited their primary care physician.2 Clearly, increasing numbers of consumers are seeking something other than conventional medical care.
While modern medicine is often focused on acute disease, many individuals living with chronic illnesses, such as cancer, acquired immunodeficiency syndrome, arthritis, pain syndromes, and chronic fatigue, are looking elsewhere for help, abandoning traditional medicine completely. Others combine conventional therapies with alternative techniques, such as homeopathy, acupuncture, diet modification, chiropractic, aromatherapy, and other interventions aimed at perceived "mind-body" links.3-4 Surprise cures and responses often remain unexplained and are attributed to complex mind-body forces4-5; yet, as these associations are described, the biological substrate to these mysteries is gaining further definition. Alternative or "holistic" medicine approaches typically lack the accepted empirically derived scientific foundations of "Western" medicine. These approaches, however, have a core unifying theme: the interconnectedness of mind and body.5 Furthermore, alternative therapies highlight the capacity of humans to respond to a range of interventions, including touch, sound, mental imagery, and fragrances.6-9 Interest in alternative therapies that incorporate mind-body concepts has grown among conventional scientists and clinicians. However, while awareness of links between mental and physical well-being grows, objectively quantifying and describing mechanisms to account for these links remains a formidable empirical task.10-12 To date, the science lags behind the practice, and explanatory models are in their rudimentary stages. One such model—the neuro-immuno-cutaneous-endocrine (NICE) network—is a simple construct featuring 4 organ systems intimately involved in the bridge between body and mind. These intimately linked systems share a language of neuropeptides, cytokines, glucocorticoids, and other effector molecules: common words used in a dynamic web of dialogue.
BIDIRECTIONALITY OF MIND-BODY INFLUENCES
From Body to Mind: Afferent Pathways in the NICE System
Few investigators and clinicians would question the impact of conventional sensory stimuli on mood and cognitive function, but only now are scientists beginning to characterize the "hidden" senses and pathways that may profoundly influence daily health and subjective well-being. For instance, physical afferent stimuli to skin, such as traction, rubbing, and scratching, can result in local stimulation, irritation, and inflammation. Immunocompetent cells stimulated by these conditions may cross the blood-brain barrier and secrete their cytokines and other inflammatory mediators, thereby directly modulating the central nervous system (CNS) as well as the local skin environment. The CNS may respond by releasing neurotransmitters and, perhaps, initiate motor behaviors directed at the skin, such as scratching and picking. As one example of such a physical connection, immobilization-induced stress in male Syrian hamsters resulted in a wide range of stress-induced end-organ effects. Plasma testosterone levels, sebaceous lipogenesis, and epithelial cell proliferation were reversibly reduced.13 A cutaneous-endocrine connection has been demonstrated in male Wistar rats anesthetized with pentobarbital that responded to nociceptive pinch stimulation of bilateral hindpaws with significantly increased plasma levels of luteinizing hormone, testosterone, and corticosterone.14-15 In vivo paracrine interactions between the immune and peripheral nervous systems have also been demonstrated. Using a rat model of adjuvant-induced local joint inflammation, the existence and activation of a local anti–nociceptive system in response to the stress of a cold water swim has been shown.  -Endorphin was produced by macrophages, lymphocytes, and plasma cells infiltrating the inflamed synovial tissue. This model suggests that immune cells, by producing neuroendocrine peptides such as -endorphin, may actually initiate or modify the perception of pain. It is possible that the immune system might constitute a sixth sense by converting stimuli from environmental factors (viruses, bacteria, trauma, tissue necrosis, etc) into "biochemical information in the form of neurotransmitters, hormones, and cytokines."16 If these factors can induce or modify pain perception, it is conceivable that they could alter other sensory perceptions,17-18 such as those inherent in the perception of beauty or unattractiveness. Perhaps these factors mediate, in part, some of the behavioral components in cycles associated with pruritus-induced19-22 scratching, neurotic excoriations, compulsive skin picking, and trichotillomania. Furthermore, many "mind-skin" types of conditions, such as self-cutting, burning, skin piercing, and so-called self-mutilation, may be postulated to be mediated, in part, through similar mechanisms via pain- and anxiety-reducing components.
From Mind to Body: Efferent Pathways
Efferent pathways provide a link between higher cortical, limbic, and CNS functions and the diverse organ systems of the body. For instance, pathways linking higher cortical function to the hypothalamic pituitary axis have been established.16 Additional evidence has accumulated to suggest numerous efferent links between the CNS and the immune system. For instance, certain areas of primary and secondary lymphoid organs, such as lymph nodes and the spleen, are innervated with noradrenergic sympathetic neuronal fibers. Finally, lymphocytes and macrophages express a wide range of hormone, neuropeptide, and steroid receptors.22
The discovery of such concrete pathways of neuroimmune modulation dovetails with the observation that chronic or repetitive mental stress seems to alter immune response.23 Clinical examples of this phenomenon abound. For instance, patients often note an exacerbation of latent herpetic infections in the context of feeling anxious or "worn down." Psychological stresses in students during examination periods may affect antibody production to hepatitis vaccine.24 Stress effects on delayed-type hypersensitivity responses, including modification of delayed-type hypersensitivity responses in depression and other nervous conditions, have also been described.25 A compromised immune system induced by environmental stimuli and nervous system responses may predispose certain individuals to cutaneous malignancies associated with viruses (eg, Kaposi sarcoma associated with human herpesvirus and human immunodeficiency virus infection; human papillomavirus associated with cervical carcinoma).
Skin as a Neuroimmunoendocrine Interface: NICE
Dermatologists and other clinicians have long recognized neuropsychological connections between skin appearance, perception of beauty, and health. Simple observations of normal expressions of these connections, such as blushing associated with strong emotions or pallor and sweating due to fear and anxiety, are well known.26 Pathological expressions of the association between nervous system perturbations and skin disease are commonly seen in clinical practice.27 Stressful life events may exacerbate psoriasis, acne, eczema, and urticaria.21, 28-29 In a survey of 5600 patients with psoriasis, Farber and Nall28 found that more than 30% of the patients believe that stress triggers their psoriatic flares, and in a companion study of 2144 patients with psoriasis, 40% of the patients associated the appearance of psoriatic plaques with concurrent life stressors.29 One report, based on a survey of patients seen in a dermatology clinic, noted that approximately 40% of the patients also had concurrent psychiatric symptoms.30 Thus, the perceived association between mental and physical well-being is strong. But how does "stress" translate into tangible cutaneous manifestations?
Traditionally, the concept of stress has been linked to physical mechanisms of cutaneous damage, such as scratching, picking, rubbing, and poor hygiene. In contrast, science has been unable to explain how an abstraction such as psychogenic stress could generate structural and functional changes predisposing skin to disease. However, recent evidence of concrete neuroanatomical links between CNS and skin reveals that some of these conceptual connections can be anatomically demarcated, thereby shedding light on the pathophysiological mechanisms of skin disease. The nervous and the immune systems share specific communication molecules that originate in both systems.31 In skin, Langerhans cells and the proximity of calcitonin gene–related peptide (CGRP) to both Langerhans cells and neurons led to consideration of bidirectional communication in skin between the immune and the nervous systems. Expression of neurotrophic factors and neuropeptide receptors by Langerhans cells gives further support to the theory that there is a functional relationship between these cells and epidermal nerves.32-33 These neuropeptides modulate bidirectional communication between the nervous and the immune systems34-35 and provide firm evidence for a mind-body connection in the skin. The application of techniques of in situ immunohistochemistry and confocal microscopy has led to the characterization of elaborate networks of cutaneous nerves containing numerous neuropeptides, many of which have intriguing properties such as vasodilatation, edema formation, and epithelial cell proliferation. A wealth of data concerning the function and distribution of these cutaneous neuropeptides has accumulated, fueling research aimed at uncovering structural and functional evidence linking stress to skin disease.
Cutaneous Neuropeptides
Neuropeptides are ubiquitous in the skin and constitute a diverse group of molecules functioning as neurotransmitters, neuromodulators, potential growth factors, and hormones. Immunohistochemical staining for various neuropeptides in the skin has shown that these molecules are present in both cutaneous nerve fibers and all cutaneous cells examined, including keratinocytes, immunocytes, fibroblasts, Langerhans cells, and endothelial cells. Comments on select neuropeptides in skin follow, with more details provided in reviews and primary articles.22 Interest has developed on the physiological and pathogenic roles of vasodilatory cutaneous neuropeptides, such as CGRP, the nociceptive neurotransmitter substance P (SP), vasoactive intestinal peptide (VIP), neuropeptide Y, and the more recently characterized pituitary adenylate cyclase activating peptide. When injected intradermally, these substances are known to induce vasodilatation, and intradermal SP produces classic wheal and flare reactions.22 Epidermal growth factor was, in retrospect, one of the first neuropeptides described. Recent studies suggest that it has a role in the development of psoriasis. The skin contains other neuropeptides with less well-defined cutaneous functions, including somatostatin, neurokinin A, neurotensin, atrial natiuretic peptide, galanin, and  -melanocyte-stimulating hormone.22, 36-37 In addition to reports on the neuropeptide properties of -melanocyte-stimulating hormone, an expanding literature on its role in immune responses has developed. Substance P is one of the cutaneous neuropeptides under investigation for its potential role in the pathogenesis of skin disease. It is part of the peptide family of tachykinins and has been identified mainly by its role in nonciceptive pathways, but it also has a putative role in tissue repair. Substance P immunoreactivity is strongest in perivascular sites and in the papillary dermis, yet changes in this distribution have inconsistently been reported for lesional and nonlesional skin in common dermatoses, such as atopic dermatitis37 and psoriasis.38 Substance P receptors are found on mast cells, neutrophils, and macrophages,22 and SP is chemotactic for mononuclear and polymorphonuclear leukocytes,39 suggesting a link between neurogenic stimuli and infiltration of the skin by inflammatory cells. Cultured normal human keratinocytes contain specific SP-binding sites,40 suggesting a link between this neuropeptide and keratinocyte activity. Calcitonin gene–related peptide has been implicated in disorders of the cutaneous microvasculature. The digital cutaneous microvasculature in patients with Raynaud phenomenon shows a deficiency of CGRP-containing nerves in the distal digital skin.41 Human suction blister injury produces an increase in PGP (a pan-neuronal marker protein) and CGRP-immunoreactive nerves as compared with controls 6 hours after injury, suggesting a relationship between epidermis, blood vessels, and nerve fibers during the tissue healing process.42 A similar increase in CGRP-immunoreactive fibers was noted in the skin of shaved rats that had been stimulated by pinching or ice water, suggesting that cutaneous stimulation can cause a rapid rise in CGRP content. Calcitonin gene–related peptide probably has crucial immunomodulatory effects in vivo, as revealed by the intimate relationship between Langerhans cells and CGRP-containing nerve fibers and the observation that CGRP inhibits Langerhans cell antigen presentation.43 Other neuropeptides likely involved in cutaneous physiology and pathophysiology include VIP and pituitary adenylate cyclase activating peptide; both peptides demonstrate potent vasodilatory activity when intradermally injected, and in vitro evidence suggests that VIP may be both mitogenic for cultured human keratinocytes and immunosuppressive, dampening experimental delayed hypersensitivity reactions.44 Pituitary adenylate cyclase activating peptide, a member of the VIP-secretin-glucagon family of ligands, shares some of VIP's cutaneous activities, including potent vasodilatation and immunomodulatory function.45 This brief survey of cutaneous neuropeptides suggests that these molecules likely play a key role as intermediary signals connecting the neuroendocrine system with immune and organ-specific processes. The neuroendocrine system may relay higher cortical "signals" via an array of processes, some circuitous and involving a cascade of steps (such as nitric oxide induction in cells adjacent to target cells), while other connections may be more direct. Shedding light on these complex pathways may be the first step toward a better understanding of how abstract cortical processes (stress) can lead to concrete manifestations, such as inflammatory disorders of the skin (atopic dermatitis, psoriasis, vitiligo, alopecia areata, etc). Although this section has focused on neuropeptides, these molecules are a small subset of intercellular messengers that likely influence cellular function in vivo. Investigation into the distributions and roles of nonpeptidergic neurotransmitters, such as catecholamines, steroids, nitric oxide, endorphins, and other small molecules, will contribute to our understanding in this area.46-48 Additional factors, such as mechanical tension on both a microlevel and a macrolevel, appear to modulate local cellular function.49
NICE Smells
While we have focused on the role of skin as an interface between environment, body, and mind, it is likely that other sensory modalities have equally profound effects on physical and mental health. How, for instance, does olfactory input influence the body and mind? Odors, scents, and fragrances have long been used in a host of rituals, including religious rites, and as primitive protective agents against infection. For example, medieval physicians wore scented masks as protection against infection with the plague.50 Acupuncture for reducing pain and bolstering the immune system is frequently used in conjunction with olfactory stimulation with incense. Furthermore, a body of literature suggests that in both therapeutic agents and appearance-enhancing cosmetics, certain odors, whether within a topical medium or delivered ambiently, can influence mood, anxiety, cognition, immune function, and, possibly, skin health.8, 51-52 Since odor molecules, like medications, stimulate signal transduction pathways via ligand-receptor interactions in peripheral and central pathways,53 it is conceivable that olfactory administration of medications in the form of fragrances could alter nervous and immune function. Aromatherapy, or the use of fragrances to enhance well-being and treat sickness, is a well-established technique of "alternative medicine."3, 7-9,50
The anatomical basis for olfactory and limbic system interconnections has been described.53 Although the mechanism of action is unclear, odor may effect mind processes via the interaction of fragrance molecules on olfactory mucosal cells with information transfer via olfactory pathways to limbic and hypothalamic structures.53 Therefore, olfactory approaches may yield a direct route into limbic system structures and thus modulate many basic human functions.53-54 Pleasing, as opposed to disagreeable, odors have a strong, immediate, and powerful effect on humans and social interactions. Even odorific molecules not consciously recognized, such as pheromones, are recognized as influential, primal means of communication among virtually all species, humans included.54-55 Odor identification, recognition, and discrimination have important survival and reproductive value,55 and deficits in olfaction have been noted in several neuropsychiatric disorders, including Alzheimer disease, Parkinson disease, schizophrenia, and depression.52-54,56-58
Since many dermatologic treatments are topical, the addition of specific olfactory cues may maximize the therapeutic value of these agents, particularly when the agents are used for conditions with strong presumptive mind-body connections (eg, allergic dermatitis, psoriasis, eczema, pruritus, urticaria atopic dermatitis, and inflammmatory dermatoses).7, 21, 51-52
CONCLUSIONS AND FURTHER DIRECTIONS
The process of mapping the tangled web connecting physical and mental well-being is underway. Could pharmacologic agents be developed for oral, topical, or intranasal (fragrant) delivery to be used in combination with techniques of tactile stimulation to ameliorate disease processes or to make persons feel better about themselves? Can these intervention pathways act at various in–roads of the NICE system to affect this still ill-defined proposed circuit?
Capsaicin has been used to alter cutaneous neuropeptide content (depletion of SP and other neuromediators from nerve terminals), thereby dampening local and systemic neuropeptide-mediated effects, such as vasodilatation, pruritus, and subjective pain.59 As individual neuropeptides and their functions are further characterized, specific agonists and antagonists may prove to have specific anti-inflammatory and vasoactive properties. For instance, a topically applied CGRP agonist may improve symptomatic Raynaud phenomenon. Topical application of vasoactive neuropeptides might produce a long-lived "natural blush." Selective neuropeptide agonists and antagonists may find utility as tools for the manipulation of local and systemic immune responses. Perhaps these compounds could modify ascending nociceptive and tactile pathways, mitigating painful impulses, while amplifying pleasurable tactile sensations.
If stressful environmental experiences can hamper immune function, could beneficial environmental manipulations improve immune function, thereby ameliorating immune-related skin conditions? For example, just as -blockers are used by many individuals to decrease autonomic arousal due to anxiety associated with a speech or musical performance, could an analogous approach decrease the likelihood of a stress-induced herpetic episode?
An even more powerful mood-modifying effect could be attained by simultaneously manipulating tactile, mental/visual imagery, olfactory modalities, and, while not discussed herein, aural stimuli. Such an approach is fundamental to holistic medicine, which emphasizes synergistic treatment using multiple methods of CNS stimulation, such as biofeedback, herbal medicine, and mechanical manipulation.
In a similar fashion, a cosmetic application containing compounds designed to induce cutaneous flushing, while enhancing tactile sensation, coupled with a pleasing fragrance, may enhance an individual's subjective well-being. Conversely, blockade of erythema or flushing by topical application of inhibitors of nitric oxide production or other vasocontrictor molecules could have analogous cosmetic applications. Although topical medications are used for a host of conditions in dermatology, no topical psychiatric medications have been developed. Perhaps this area holds promise for future development.
Restorative fragrances, whether in cosmetics or perfumes, have only begun to be applied in settings other than cosmesis. Cosmetics are typically used to enhance appearance, a sense of youthfulness, and self-esteem. Studies noted herein have suggested that scents have positive effects on function, mood, and anxiety. Because many skin conditions have a multifactorial origin, including psychiatric components, combined treatment with psychotropic scents and creams in conjunction with visualization and autohypnotic techniques may prove beneficial in select clinical settings.6-8,51, 53, 58-59
In conclusion, an attempt has been made to synthesize literature from various disciplines regarding NICE connections relevant to mind-body interactions in dermatology. Neuropeptides and other still poorly characterized messengers may serve as important communication molecules mediating nervous, immune, and skin health. Appearance, although often relegated to a minor concern in overall health, plays a crucial role in the maintenance of self-esteem and mental and physical health. Dermatologists play a critical role in maintaining and improving skin health and appearance and can play a pivotal role in recognizing and exploiting these interactions clinically. The interconnections described herein suggest a window into brain functioning, immune system, and skin health that we are only starting to fathom. Some of the studies outlined above suggest that seemingly trivial perturbations, such as tactile nociceptive and olfactory stimulation, might have profound neuroendocrine effects. The simplest of tamperings may ultimately influence the very substrate of the human mind.
AUTHOR INFORMATION
Accepted for publication August 5, 1998.
The authors would like to thank John Parrish, MD, Richard Granstein, MD, Rebecca Campen, MD, Ned Cassem, MD, Scott Rauch, MD, and Nancy Etcoff, PhD, for helpful comments on earlier drafts of the manuscript for this article.
Reprints: Ethan A. Lerner, MD, PhD, MGH-CBRC, Bldg 149, CNY-4, 13th Street, Charlestown, MA 02129.
From the Department of Psychiatry, Massachusetts General Hospital Psychiatric Neuroscience Program (Dr O'Sullivan), and the Department of Dermatology, Massachusetts General Hospital–Harvard Cutaneous Biology Research Center (Drs Lipper and Lerner), Charlestown, Mass, and the Departments of Psychiatry (Dr O'Sullivan) and Dermatology (Drs Lipper and Lemer), Harvard Medical School, Boston, Mass.
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