Mast cell tryptases and chymases in inflammation and host defense

Abstract

Tryptases and chymases are the major proteins stored and secreted by mast cells. The types, amounts, and properties of these serine peptidases vary by mast cell subtype, tissue, and mammal of origin. Membrane-anchored gamma-tryptases are tryptic, prostasin-like, type I peptidases that remain membrane attached on release and act locally. Soluble tryptases, including their close relatives, mastins, form inhibitor-resistant oligomers that act more remotely. Befitting their greater destructive potential, chymases are quickly inhibited after release, although some gain protection by associating with proteoglycans. Most chymase-like enzymes, including mast cell cathepsin G, hydrolyze chymotryptic substrates, an uncommon capability in the proteome. Some rodent chymases, however, have mutations resulting in elastolytic activity. Secreted tryptases and chymases promote inflammation, matrix destruction, and tissue remodeling by several mechanisms, including destroying procoagulant, matrix, growth, and differentiation factors and activating proteinase-activated receptors, urokinase, metalloproteinases, and angiotensin. They also modulate immune responses by hydrolyzing chemokines and cytokines. At least one chymase protects mice from intestinal worms. Tryptases and chymases can also oppose inflammation by inactivating allergens and neuropeptides causing inflammation and bronchoconstriction. Thus, like mast cells themselves, mast cell serine peptidases play multiple roles in host defense, and any accounting of benefit versus harm is necessarily context specific.

Fig. 1. Summary of targets of pro-inflammatory actions of mast cell tryptases and chymases

1) Soluble β-tryptases stimulate nerves by activating proteinase-activated receptor 2 (PAR2) and 2) affect airway smooth muscle and fibroblasts by acting as mitogens and by promoting secretion of matrix proteins. They also 3) recruit neutrophils and eosinophils and degranulate mast cells, 4) provoke airway epithelial cells to produce interleukin-8, 5) degrade extracellular matrix and fibrin clots by activating pro-stromelysin and pro-urokinase, respectively, and 6) stimulate endothelial cells to form vessels. Chymases overlap tryptases in some of their targets, but with unique effects, including the following: 7) they alter arterial caliber and intimal responses to injury by generating angiotensin II and promote new vessel growth by activating pro-MMP-9; 8) they degrade matrix proteins directly (as well as indirectly by activating pro-MMP-9); they may alter epithelial growth and repair by degrading hepatocyte growth factor; 10) they may affect the properties of mucus by degrading serous cell proteoglycans and 11) also stimulate gland cell secretion itself.

Fig. 2. Cutaneous example of an anti-inflammatory effect of mast cell serine peptidases

Skin trauma stimulates dermal sensory nerves, which propagate antegrade and retrograde impulses and liberate inflammatory neuropeptides such as substance P and calcitonin gene-related peptide (CGRP). The latter is a potent vasodilator contributing to the flare reaction surrounding sites of injury. Tryptase released from local mast cells by substance P cleaves and inactivates CGRP, thereby shortening duration of the flare.