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.

Cutaneous‐immuno‐neuro‐endocrine (CINE) system: A complex enterprise transforming skin into a super organ

“…Interestingly, mast cells may secrete mediators 'without actual degranulation' by a process called 'intragranular activation'. 2 This is said to be made possible due to selective release of key molecules such as serotonin, TNFα and vascular endothelial growth factor (VEGF) by mast cells. [45][46][47] Mast cells also drive Tcell activation via TNFα and activation of proteinase-activated receptors (PARs) on CSANs, resulting in modulation of neurogenic inflammatory response.…”

“…Mast cells are key players in stress‐induced neurogenic inflammation and CINE loop. They are situated in close proximity with CSANs (responsible for secreting substance P, SP and calcitonin‐gene related peptide, CGRP) as well as blood vessels and exert innate immunoregulatory effects 2,43 . Their strategic anatomical location makes them allow convergence of the three super systems within the skin.…”

“…Mast cells in turn, secrete a vast pool of ‘pre‐formed’ and ‘newly synthesized’ proinflammatory mediators like histamine, vasoactive intestinal peptide (VIP), TNF‐α, kinins, proteases, chemokines and cytokines. Interestingly, mast cells may secrete mediators ‘without actual degranulation’ by a process called ‘intragranular activation’ 2 . This is said to be made possible due to selective release of key molecules such as serotonin, TNF‐α and vascular endothelial growth factor (VEGF) by mast cells 45–47 .…”

“…This delicate yet highly efficient sensory functioning of skin is the result of the common embryonic roots between skin and nervous system (both being derived from ectoderm). Further, the close interplay between various neuromediators at different levels serves to transform cutaneous system into a highly specialized neuro‐immune‐endocrine organ 1,2 . Recent studies demonstrate that cutaneous sensory nervous system, in addition to relaying signals to CNS, also contributes to cutaneous immunity and inflammation 3,4 .…”

“…Further, the close interplay between various neuromediators at different levels serves to transform cutaneous system into a highly specialized neuroimmune-endocrine organ. 1,2 Recent studies demonstrate that cutaneous sensory nervous system, in addition to relaying signals to CNS, also contributes to cutaneous immunity and inflammation. 3,4 Under physiological conditions, the sensory neurons and native skin cells cooperate to maintain the immune function of skin along with monitoring any inflammatory response generated, leading to effective modulation of transient neurogenic inflammation.…”