Neuroimmunocutaneous System Research Articles

The importance of the neuro-immuno-cutaneous system on human skin equivalent design.

The skin is a highly complex organ, responsible for sensation, protection against the environment (pollutants, foreign proteins, infection) and thereby linked to the immune and sensory systems in the neuro‐immuno‐cutaneous (NIC) system. Cutaneous innervation is a key part of the peripheral nervous system; therefore, the skin should be considered a sensory organ and an important part of the central nervous system, an ‘active interface’ and the first connection of the body to the outside world. Peripheral nerves are a complex class of neurons within these systems, subsets of functions are conducted, including mechanoreception, nociception and thermoception. Epidermal and dermal cells produce signalling factors (such as cytokines or growth factors), neurites influence skin cells (such as via neuropeptides), and peripheral nerves have a role in both early and late stages of the inflammatory response. One way this is achieved, specifically in the cutaneous system, is through neuropeptide release and signalling, especially via substance P (SP), neuropeptide Y (NPY) and nerve growth factor (NGF). Cutaneous, neuronal and immune cells play a central role in many conditions, including psoriasis, atopic dermatitis, vitiligo, UV‐induced immunosuppression, herpes and lymphomas. Therefore, it is critical to understand the connections and interplay between the peripheral nervous system and the skin and immune systems, the NIC system. Relevant in vitro tissue models based on human skin equivalents can be used to gain insight and to address impact across research and clinical needs.

Human Skin Equivalents Demonstrate Need for Neuro-Immuno-Cutaneous System.

A variety of human skin equivalents (HSEs) has been designed for clinical use or for exploratory skin research. In vitro HSE models have been used to target relationships between the skin and nervous or immune systems but have not yet considered the neuro-immuno-cutaneous (NIC) system. In this study, HSEs are described, with and without neural and immune components, to discern these types of effects. These systems are composed of only primary human cells and contain an epidermis, dermis, hypodermis (with immune cells), and human induced neural stem cells for the neuronal component. RNA sequencing is utilized to confirm differences between sample groups and to identify unique or important genes with respect to sample type. Only samples with both neural and immune components result in the upregulation of genes in all the key biological pathways explored. The analysis of protein secretion confirms that this group has measurable functions related to all key cell types. Overall, this novel skin tissue system confirms that designing HSEs that include the NIC system results in a tissue model that reflects key functions. These systems could be used to identify selected targets of interest in skin research related to healthy or diseased states.

The Role of Psychodermatology in Acne Vulgaris Pathophysiology

1. Abstract Acne Vulgaris (AV) is a common skin disease, affecting over 90% of male adolescent and about 80% of female adolescent in all ethnic groups. It causes both physical and psychological disorders. Its pathophysiology is multifactorial interplay of hormonal imbalance, increased sebum production, bacterial colonization, and neuropeptides that plays a major role. Acne vulgaris is a visible skin disease and commonly occurs in adolescent, therefore it is relevant to understand AV correlation with psychosocial and psychoneuroimmunology factors. Due to adolescent is a significant and vulnerable phase of life to the various stressor, it is also transition time from the immaturity of childhood into the maturity and independent of adulthood. Psychodermatology addresses the interaction between mind and skin. Psychiatry is more focused on the ‘internal’ non-visible disease, and dermatology refers to the presence of morphological abnormalities appear in the skin, where connecting the two disciplines is a complex interplay described as Neuro-Immuno-Cutaneous System (NICS). Facial skin from AV patients show marked increase of substance P-positive nerve fibers around the sebaceous glands and around acne lesions. Substance P induces gene expression of Peroxisome Proliferator-Activated Receptor (PPAR)- γ , which plays a unique role in stimulating sebocyte lipogenesis. It also stimulates various pro-inflammatory cytokines release from sebocytes, including IL-1, IL-6, and TNF- α . The interaction between nervous system, skin and immunity has been explained by discovered of various release of mediators or cytokines from NICS. There is no doubt that AV can lead to anxiety and stress, hence the patients may experience social issue and decreased quality of life. 2. Keywords: Acne vulgaris; Neuro-immuno-cutaneous system; Psychodermatology; Quality of life

Skin matters: identifying pain mechanisms and predicting treatment outcomes.

The skin acts as a complex sensory organ. The emerging new data on peripheral pain mechanisms from within the skin is presented. This data has led to new insights into the potential pain mechanisms for various pain conditions including neuropathic pain (from small fiber neuropathies) and Complex Regional Pain Syndrome. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 channels and voltage-gated sodium channels are critical for pain transmission. Epidermal cells (such as keratinocytes, Langerhans cells, and Merkel cells) express sensor proteins and neuropeptides; these regulate the neuroimmunocutaneous system and participate in nociception and neurogenic inflammation. In the past two decades, there has been widespread use of modalities such as punch skin biopsies, quantitative sensory testing, and laser-evoked potentials to evaluate small caliber nerve fibers. This paper explores these laboratory techniques as well as the phenomenon of small fiber neuropathy. Treatment using transdermal drug delivery is discussed. There is potential for these findings to predict treatment outcomes in clinical practice and to develop new therapies for different pain conditions. These findings should enhance the physician's ability to evaluate and treat diverse types of pain.

The role of the skin in peripheral neuropathic pain

SUMMARY In addition to homeostatic and immunologic barrier functions, the skin acts as a complex sensory organ. Traditionally, the sensory modality of pain was thought to be transduced exclusively by primary afferent neurons, but the concept of a neuro-immuno-cutaneous system (NICS) is becoming more recognized. This system involves signals between both neuronal and non-neuronal skin cells. The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor plays an important role in the NICS. It is highly expressed on nociceptive sensory nerves, as well as on non-neuronal skin cells, especially keratinocytes. Keratinocytes, which account for 85% of the cells of the dermis, have a close anatomic relationship with peripheral nerves and have TRPV1 receptors on their surface. TRPV1 receptors have also been reported on Langerhans cells, sebocytes and sweat gland epithelium, although due to different staining techniques there is controversy about the actual amount. TRPV1 receptors are activated by capsaicin and the topical application of a high-concentration capsaicin patch has been shown to significantly reduce pain in patients with post-herpetic neuralgia or HIV-associated neuropathy. Given the emerging picture of the role played by cutaneous cells in pain transmission, this review will discuss the critical interplay between cutaneous cells and nociceptors, and how their interactions contribute to the pathophysiology of peripheral neuropathic pain.

Nerve growth factor, neuropeptides and cutaneous nerves in atopic dermatitis

Introduction:Neurogenic components, as neurotrophic factors and neuropeptides, are probably involved in the pathogenesis of atopic dermatitis (AD) with the neuroimmunocutaneous system as they modify the functions of immunoactive cells in the skin. Nerve growth factor (NGF) is the best-characterized member of the neurotrophin family. Both NGF and neuropeptides (NPs) may be associated with the disease pathogenesis.Aim:This study aims to evaluate the plasma level of NGF and NPs in AD patients and correlate them with the disease activity and nerve changes in the skin by electron microscopy.Materials and Methods:Plasma levels of NGF and vasoactive intestinal peptide (+VIP) were measured by an immunoenzymatic assay while plasma levels of calcitonine gene related peptide (CGRP) and neuropeptide Y (NPY) were measured by radioimmunoassay in 30 AD patients in comparison to 10 normal non-atopic controls. Electron microscopic study was done in 10 AD patients.Results:It has been found that there is significant increase of plasma levels of NGF and NPs in AD patients compared with controls. There is a positive correlation between the plasma levels of NGF and disease activity (correlation coefficient = 0.750, P<0.005). There is a significant correlation between the number of Schwann axon complex, evidenced by electron microscopic examination and plasma level of NGF in AD patients.Conclusion:It has been concluded that these neurogenic factors; NGF and NPs modulate the allergic response in AD, probably through interactions with cells of the immune-inflammatory component. NGF might be considered as a marker of the disease activity.

The whole epidermis as the forefront of the sensory system

Please cite this paper as: The whole epidermis as the forefront of the sensory system. Experimental Dermatology 2007; 16: 634–635. Skin is a major sensory organ. The awareness of the external environment goes through molecular receptors. We were highly interested in the paper from Denda (1), which proposes the concept of ‘epidermal keratinocytes as the forefront of the sensory system’. The authors suggest that keratinocytes are able to recognize environmental factors and then the information is processed and conveyed to the nervous system. Keratinocytes are equipped with sensing systems similar to those of neurons: (i) they express sensory receptors like the transient receptor potential (TRP) family or the ATP receptors; (ii) the stimulation of these receptors is followed by signal transduction and release of neurotransmitters by keratinocytes, whereas an electrochemical communication is possible due to the presence of voltage-gated channels; (iii) keratinocytes are able to process information from the nervous system through ionotropic and G-protein-coupled receptors for neurotransmitters. The close interactions between skin and nerve endings have lead to define integrated systems, which have been called skin-neuroendocrine system (2) or neuro-immunocutaneous system (3). These interactions are strongly enhanced by the existence of synapses between epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells) and neurons (4). But all these neuron-like properties are not restricted to keratinocytes.

Les nerfs à fleur de peau

Skin innervation is extremely dense and reaches the most superficial layers of the epidermis (but not into the stratum corneum). The relationship between skin and the nervous system was neglected for a long time. Nowadays, this represents one of the most widely investigated fields of skin biology. Associations between nerve fibres and skin are so close that these can be observed at the cellular level. They are anatomical and physiological. Neurotransmitters are naturally synthesized by nerve endings, but cells from the skin and the immune system are also able to produce them. They are mediators for transmission of information between skin and the nervous system. All cutaneous and immune cells express specific receptors for these neuromediators, and enzymes for degrading them. Binding of the neurotransmitter to its receptor induces modulation of cell properties and skin functions (immunity, cell differentiation and proliferation, pigmentation, etc.). Hence, keratinocytes, Langerhans cells, melanocytes, endothelial cells, fibroblasts and the other cells of the skin or the immune system are modulated and controlled by the nerves. Reciprocally, skin is able to modulate neuronal activity and growth. All these data suggest that skin, nervous and immune systems are integrated in a unique system that we could name the neuro-immuno-cutaneous system (NICS). Hence, we can understand how the nervous system, and further the psychism, are involved in the maintenance of cutaneous homeostasis. In dermatological diseases or in cosmetological disorders, this equilibrium is broken. New fields of research are open: neuro-dermatology and of course neuro-cosmetics. Neuro-cosmetic products are supposed to modulate NICS functioning at the epidermal level. The French expression 'avoir les nerfs à fleur de peau' means that nervosity is so tense that one feels his nerves closely under or within skin, ready to explode. In fact, nerves are always 'à fleur de peau'. Skin is an organ whose dense innervation involves the outermost skin layers, stratum corneum excepted. Long time neglected, the relation between skin and the nervous system are, today, a growing field of research within cutaneous biology.

Neuropeptides in atopic dermatitis

The nervous system, the immune system, and the cutaneous system are not independent systems, but are closely associated and use the same language of cytokines and neurotransmitters. Atopic dermatitis (AD) is exacerbated by several factors, such as emotional stress, scratching and sweating. This review presents the role of neuropeptides (NP) in AD. In AD, abnormalities occur in distribution of some types of neural filaments and in the associated active NP. Nerve fibre increases. Nerve fibres for substance-P (SP) and calcitonin gene-related peptide (CGRP) are positive, The cutaneous concentration of SP decreases while vasoactive-intestinal polypeptide (VIP) increases. Immunohistochemical examination has revealed neuropeptide-Y (NPY)-positive dendritic epidermal cells in AD lesions but no somatostatin (SOM) fibres. Neuromediators modulate functions of all cutaneous cellular types, which are all part of the neuroimmunocutaneous system (NCIS): endothelial cells, glandular cells, fibroblasts, epidermal cells and immune cells. Conclusion: during the course of AD, the NICS is destabilized. Evidence show that NP can also be responsible for the induction and maintenance of the cutaneous inflammation process and confirm an involvement in the pathogenesis of AD. Release of the NP by cutaneous nerve potentially explains the role of emotional stress, scratching and sweating in exacerbation of AD. (Med J Indones 2001; 10: 197-200)

The neuro-immuno-cutaneous system and ultraviolet radiation.

Numerous cells are closely associated with cutaneous nerve fibers, which through the action of neuropeptides are able to modulate cellular function. Anatomical and physiological links between immune cells and nerves and other cells in skin are so close that we propose the concept of a neuro-immuno-cutaneous system (NICS). Under the impact of ultraviolet radiation (UVR) virtually all properties of the NICS are modified. UVR induces melanin synthesis and immunosuppression, events in which neuropeptides, especially melanocyte stimulating hormone (MSH) and the calcitonin gene-related peptide CGRP, play a role.

Langerhans cells in the neuro-immuno-cutaneous system

Langerhans cells are epidermal antigen presenting cells. They are able to express some neuronal markers. They express many neuropeptide receptors. Neuropeptides are able to modulate Langerhans cell functions. Langerhans cells are closely connected with nerve fibers in the epidermis. Thus, Langerhans cells and the nervous system are anatomically and functionnaly associated. We suggest that they belong to a neuroimmunocutaneous system. The interactions between nervous and immune system are probably important in the pathophysiogeny of inflammatory dermatoses.

Skin, immunity and the nervous system

Connections between nerve fibres and cutaneous cells have been studied using confocal and electron microscopy. In the skin, nerve fibres may secrete neuromediators, i.e. substance P, vasoactive intestinal peptide, somatostatin, calcitonin-gene-related peptide, gastrin-releasing peptide, neuropeptide Y, peptide histidine-isoleucine, neurotensin, neurokinins A and B, bradykinin, acetylcholine, catecholamines, endorphins and enkephalins. Neurohormones such as prolactin, melanocyte-stimulating hormone and adrenocorticotrophic hormone are also expressed in the skin. Neuromediators and neurohormones may be secreted by cutaneous cells, which also express receptors. Functions of epidermal and dermal cells are modulated by these substances. Immune cells transiently present in the skin (e.g. macrophages and lymphocytes) are modulated by neuromediators through receptors. During the course of skin disorders, especially inflammatory reactions, the neuroimmunocutaneous system is destabilized. This is particularly true in psoriasis. This destabilization may be secondary, although evidence shows it can also be responsible for the induction and maintenance of the inflammatory process. The skin, the nervous system and immunity are not independent systems but are closely associated and use the same language of cytokines and neurotransmitters. A new concept is suggested: the neuroimmunocutaneous system.