Mast cells: versatile gatekeepers of pain

Abstract

Mast cells are important first responders in protective pain responses that provoke withdrawal from intense, noxious environmental stimuli, in part because of their sentinel location in tissue-environment interfaces. In chronic pain disorders, the proximity of mast cells to nerves potentiates critical molecular cross-talk between these two cell types that results in their synergistic contribution to the initiation and propagation of long-term changes in pain responses via intricate signal networks of neurotransmitters, cytokines and adhesion molecules. Both in rodent models of inflammatory pain and chronic pain disorders, as well as in increasing evidence from the clinic, it is abundantly clear that understanding the mast cell-mediated mechanisms underlying protective and maladaptive pain cascades will lead to improved understanding of mast cell biology as well as the development of novel, targeted therapies for the treatment and management of debilitating pain conditions.

Keywords: Cytokines; Mast cells; Neurons; Pain.

Figure 1. Mast cell-nerve proximity in the tissue facilitates neuro-immune cross-talk relevant to modulation of pain

Mast cell-nerve interactions are facilitated by adhesion molecules E-Cadherin, CADM-1, and N-Cadherin [62, 63]. Both mast cells and neurons have the potential to secrete nerve growth factor (NGF) and substance P (SP) that bind trkA, and NK-1 receptors, respectively [3]. NGF and SP participate in nociceptive signaling. NGF and tumor necrosis factor-α (TNF- α) secreted by mast cells induce neuronal growth, and reduce subsequent neuronal firing threshold through binding with trkA and TNFR, respectively [55, 65, 66, 67]. Tryptase released by mast cells binds to proteinase-activated receptor 2 (PAR2) on neurons, and initiates a cascade involving TRPV1/4 activation via PLC and release of CGRP [72, 73]. CGRP in turn binds to a G-protein coupled receptor (CGRP-GPCR) on mast cells, and promotes histamine release [74, 75]. [Artwork: John Koenig]