Do Mast Cells Have a Role in Tendon Healing and Inflammation?

Abstract

Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon homeostasis/pain after tissue damage is crucial in developing novel therapeutics for human tendon disorders. The inflammatory mechanisms that are operative in response to tendon injury are not fully understood, but it has been suggested that inflammation occurring in response to nerve signaling, i.e., neurogenic inflammation, has a pathogenic role. The mechanisms driving such neurogenic inflammation are presently not clear. However, it has recently been demonstrated that mast cells present within the injured tendon can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling and thereby modulate neurogenic inflammation following tissue injury. In this review, we discuss the role of mast cells in the communication with peripheral nerves, and their emerging role in tendon healing and inflammation after injury.

Keywords: inflammation; mast cells; neuropeptides; tendon healing; tendon pain.

Figure 1

Phases of tendon healing: inflammation, repair, and remodeling. During the inflammatory phase, immune cells (macrophages, neutrophils, and mast cells) predominate. The inflammatory phase is followed by the proliferation or repair phase where fibroblasts produce collagens and extracellular matrix components. The proliferation phase is followed by a remodeling phase, in which the tendon modifies its internal structure.

Figure 2

Mast cells are activated by multiple stimuli and secrete both preformed and de novo-synthesized mediators in response to activation. SP, substance P; CGRP, calcitonin gene-related peptide; PAMP, pathogen-associated molecular pattern; GF, growth factors, CR, complement receptor; MRGPRX2, Mas-related G-protein coupled receptor member X2; NMDAR, N-methyl-D-aspartate receptor; PG, prostaglandin; LT, leukotriene; VEGF, vascular endothelial growth factor; NGF, nerve growth factor; SCF, stem cell factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor.

Figure 3

A possible role of mast cells in regulating the inflammatory and healing responses in the injured tendon. After tendon injury, peripheral nerve endings can release neuropeptides, e.g., glutamate and substance P, that may activate mast cells or fibroblast-like cells (tenocytes) via their respective receptors, e.g., glutamate receptors (e.g., NMDAR1) NK1 and MRGPRX2. Activated tenocytes can proliferate and increase their type-I and type-III collagen synthesis during tendon healing. Activated mast cells can release proteases, e.g., tryptase, which may have a functional impact on tendon cells or may activate nearby nerves via PAR-2. Mast cells can also activate nerves via their release of histamine, which can bind to histamine receptors on nerve endings. Further, mast cells can also affect angiogenic processes. The upper right panel shows the colocalization of NMDAR1 with tryptase in vivo in injured tendon; the lower right panel shows colocalization of glutamate and NDMAR1 in glutamate-stimulated mast cells. The upper left image depicts the close localization of mast cells to blood vessels in injured tendon.