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

Abstract

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.

Peripheral Mechanisms of Neuropathic Pain—The Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain

“…The functional, structural, and molecular changes induced by peripheral nerve injury occur not only in neurons (both sensory and autonomic) and glial cells, but in non-neuronal cells (keratinocytes; immunocompetent cells-macrophages, mast cells, neutrophils), participating in modulating sensory transduction in the periphery, which have been characterized in several preclinical models [28,56,59,62,64,86,87,[101][102][103]. Upon physiological conditions, neuronal and non-neuronal cells in the periphery create a complex interplay on Figure 2, interacting by each other by released neuropeptides, cytokines, and neurotransmitters, acting on corresponding ion channels and receptors.…”

“…In the epidermis, the outermost layer of the skin, sensory nerve endings interact with other skin cells (keratinocytes and immune cells) in several ways, either via neurotransmitters, neuropeptides, and cytokines, or via membrane associations. The anatomical and functional interactions between neuronal and non-neuronal cells in the skin are contributing to nociception, neuronal hyperexcitability and peripheral sensitization [85,86]. The keratinocytes, which constitute 90% of epidermis cells, are one of the main targets of topically applied analgesics.…”

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review

“…Upon physiological nociception, peripheral neurons exert complex interactions with immunocompetent cells and keratinocytes via neuropeptides, neurotransmitters, cytokines, and other signaling molecules acting on corresponding ion channels or receptors ( Figure 1 ) [ 12 ]. Once pathological conditions (i.e., nerve injury, inflammation) occur, these interactions result in overactivation and disturbed functioning of neuronal and non-neuronal cells, finally contributing to neuronal hyperexcitability, peripheral sensitization, and pain [ 11 ].…”

Pharmacological activation of PPAR‐γ: a potential therapy for skin fibrosis

“…The multilayered skin protects the body from a variety of environmental insults and performs several physiological roles including excretion, secretion, thermoregulation, and sensation. The outer epidermis is avascular and mainly made up of keratin and growth factor secreting keratinocytes of several layers and directly faces the environmental insults such as heat, cold, and germs 1 . Genetic alterations and molecular abnormalities in keratinocytes may lead to nonmelanoma skin cancer such as actinitic keratosis and invasive cutaneous squamous cell carcinoma 2 .…”