Role of Mast Cells in the Pathogenesis of Pruritus in Mastocytosis

Abstract

Pruritus can be defined as an unpleasant sensation that evokes a desire to scratch and significantly impairs patients' quality of life. Pruritus is widely observed in many dermatoses, including mastocytosis, a rare disease characterized by abnormal accumulation of mast cells, which can involve skin, bone marrow, and other organs. Increasing evidence highlights the role of mast cells in neurogenic inflammation and itching. Mast cells release various pruritogenic mediators, initiating subsequent mutual communication with specific nociceptors on sensory nerve fibres. Among important mediators released by mast cells that induce pruritus, one can distinguish histamine, serotonin, proteases, as well as various cytokines. During neuronal-induced inflammation, mast cells may respond to numerous mediators, including neuropeptides, such as substance P, neurokinin A, calcitonin gene-related peptide, endothelin 1, and nerve growth factor. Currently, treatment of pruritus in mastocytosis is focused on alleviating the effects of mediators secreted by mast cells. However, a deeper understanding of the intricacies of the neurobiology of this disease could help to provide better treatment options for patients.

Fig. 1

Flowchart of PubMed database search.

Fig. 2

Proposed model of the functional interaction between mast cells and the synapse of the sensory nerve in the skin. Immunoglobulin E (IgE) bounds antigens (different allergens) and triggers the IgE receptor FcεRI signalling pathway, which results in mast cell degranulation. Mast cells release various mediators, such as chymase, tryptase, serotonin, histamine, and interleukins (including interleukin (IL)-31). Transmitters released from mast cells interact with their specific receptors (protease-activated receptor (PAR-2), serotonin receptor 5HTR, histamine receptor (HR), interleukin 31 receptor (IL-31R)) on nerve terminals, which leads to direct activation of pruriceptors. Stimulation of PAR-2 receptors leads to coactivation of transient receptor potential channels (TRP channels). In turn, activated nerve fibres release several mediators, including neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P, nerve growth factor (NGF) and neurokinin 1, which elicit feedback activation of the mast cell through respective receptors (Masrelated G protein-coupled receptor-X2 (MGPRX2), neurokinin 1 receptor (NK-1R), tropomyosin receptor kinase A (TrkA)). CALCRL/RAMP1: calcitonin receptor-like receptor/receptor activity-modifying protein 1; DRG: dorsal root ganglion.