Mast Cells and Sensory Nerves Contribute to Neurogenic Inflammation and Pruritus in Chronic Skin Inflammation

Abstract

The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves. These include, e.g., H1- and H4-receptors, protease-activated receptor-2, IL-31 receptor, and the high-affinity receptor of nerve growth factor (TrkA). On the other hand, sensory nerves can release neuropeptides, including substance P and vasoactive intestinal peptide, that are able to stimulate mast cells to release mediators leading to potentiation of the reciprocal interaction, inflammation, and itch. Even though mast cells are well recognized for their role in allergic skin whealing and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role for mast cell-sensory nerve communication in consequent pruritus. Therefore, we summarize here the present literature pointing to a close association between mast cells and sensory nerves in pruritic skin diseases as well as review the essential supporting findings on pruritic models in mice and rats.

Keywords: itch; mast cell; pruritus; sensory neuron; skin.

FIGURE 1

A hypothetical model for the communication between mast cells (two mast cells shown in purple) and sensory nerves (shown in gray) in neurogenic inflammation in the skin. The neuroendocrine and neural systems are activated as a consequence of psychosocial stress. The signals traveling through C-fibers lead to the release of neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), from C-fiber endings. The increased cutaneous blood flow conveys corticotropin-releasing hormone (CRH) to the developing inflammation. These neuroendocrine factors activate mast cells through the receptors NK-1R, VPAC2, MRGPRX2, and CRH-R1. Tryptase (Try), histamine (Hist), NGF, IL-31 released from mast cells activate their corresponding receptors PAR-2, H1R, TrkA, and IL-31RA, respectively, on C-fibers. Furthermore, mast cells themselves are activated through PAR-2 and TrkA in an auto- or paracrine fashion. Mast cell-derived mediators activate C-fibers leading to the spread of signal, which can also take place through an axon reflex-related mechanism. NGF and IL-31 support the growth of C-fibers. Chymase released from mast cells is susceptible to the inactivation by serum protease inhibitors, α₁-proteinase inhibitor (α₁-PI) and α₁-antichymotrypsin (α₁-AC), resulting in inactivated chymase (iChy) that cannot degrade and inactivate SP. PAR-2 can sensitize the capsaicin receptor (TRPV-1) in C-fibers enhancing SP and CGRP release. The intimate functional and morphologic communications between mast cells and C-fibers are further strengthened by the cell adhesion molecule-1 (CADM-1) on mast cells and nectin-3 on C-fibers. As a consequence of these multiple interactions, a feedforward loop is developed, which leads to increase in mast cells and C-fibers, development of vicious circle, and potentiation of neurogenic inflammation and itch.