Molecular Mechanisms of Neurogenic Inflammation of the Skin

Abstract

The skin, including the hypodermis, is the largest body organ and is in constant contact with the environment. Neurogenic inflammation is the result of the activity of nerve endings and mediators (neuropeptides secreted by nerve endings in the development of the inflammatory reaction in the skin), as well as interactions with other cells such as keratinocytes, Langerhans cells, endothelial cells and mast cells. The activation of TRPV-ion channels results in an increase in calcitonin gene-related peptide (CGRP) and substance P, induces the release of other pro-inflammatory mediators and contributes to the maintenance of cutaneous neurogenic inflammation (CNI) in diseases such as psoriasis, atopic dermatitis, prurigo and rosacea. Immune cells present in the skin (mononuclear cells, dendritic cells and mast cells) also express TRPV1, and their activation directly affects their function. The activation of TRPV1 channels mediates communication between sensory nerve endings and skin immune cells, increasing the release of inflammatory mediators (cytokines and neuropeptides). Understanding the molecular mechanisms underlying the generation, activation and modulation of neuropeptide and neurotransmitter receptors in cutaneous cells can aid in the development of effective treatments for inflammatory skin disorders.

Keywords: molecular mechanisms; neurogenic inflammation.

Figure 1

In the neurogenic inflammatory pathway, peripheral nerve endings communicate with various skin cells, such as keratinocytes, melanocytes, fibroblasts and MCs, and also with immune cells via neurotrophins and neuropeptides. In neurogenic inflammation, an important role is played by MCs, on the surface of which there are numerous receptors for neuropeptides secreted by nerve endings. After activation of the receptors, mast cells degranulate and release proteases, cytokines and histamine. Tryptase binds to the PAR-2 receptor, activating it and releasing neuropeptides such as CGRP and SP, which are responsible for itching and scratching. PAR-2 activation is associated with pain perception. Tryptase directly affects CGRP, causing its degradation and negative feedback. On the other hand, SP, acting on the NK-1R and MRGPRX2 receptors on mast cells, activates them, causes cell degranulation and intensifies the inflammatory response. This response also involves TH2CD4+ immune cells that release cytokines IL-4, IL-13 and IL-31; these cytokines, as mediators, activate receptors on nerve endings, which intensifies itching in skin diseases. Ca²⁺-dependent TRPV1 and TRPA1 ion channels can communicate with each other and, when activated, increase the release of neuropeptides, thereby exacerbating neurogenic skin inflammation.

Figure 2

The role of stress and mediators produced by cells of the nervous system, immune system and resident cells of the skin in the induction and exacerbation of symptoms of chronic dermatitis and the formation of disorders of specific and non-specific immunity of the skin.

Figure 3

The central and peripheral axes of the HPA are in charge of proper skin barrier function and inflammatory reactions. The release of neuromediators (CRF) from the hypothalamus and other areas of the CNS that can stimulate the release of norepinephrine and cortisol from adrenal HPA, and the release of leukocytes in the circulatory system via CRF and MC receptors, which modulate immune responses during inflammation and immunity, are activated by various stressors. Inflammatory responses in the skin are modulated by cytokines and neuropeptides of immune cells. Protease-activated receptor 2 (PAR2) on the plasma membrane of sensory nerve endings is activated by tryptase from degranulated MCs, which, in turn, stimulates the release of calcitonin gene-related peptide and tachykinins from sensory nerve endings. Vasoactive sensory nerve peptides are released under the influence of mediators from mast cells and other inflammatory cells. The mobilization of intracellular Ca²⁺ by PAR -2 at the level of the spinal cord induces the secretion of CGRP and SP from the central nerve endings. Neuromediators that are released when stimulated by sensory nerves modulate cutaneous inflammation, pain and itching.