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.

Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules

“…The role of mast cells in the self-defense system has been well established (31,32,40,41). For instance, mast cells sense the type 1 fimbriae of E. coli through surface-expressed CD48, resulting in release of the potent neutrophil chemoattractant TNF-a in a process that is pivotal for elimination of the bacteria (42).…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Mast cells represent potential sources of many mediators that can enhance or suppress the development, survival, proliferation, migration, maturation, or function of immune cells (reviewed in REFS [1][2][3][5][6][7][8]13,[16][17][18]21,30,31,43,44,[46][47][48][49][50][51][52][53][54][55][56]. Some individual mediators, such as histamine, can have both positive and negative immunomodulatory effects.…”

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5

“…The lectin and alternative pathways could be involved, but several proteolytic enzymes outside of these complement pathways also can generate anaphylatoxin-like activity, including thrombin, elastase, monocyte protease, kallikrein, and house dust mite protease (5)(6)(7)(8)(9)(10). Mast cells are known to be activated in asthma (11)(12)(13)(14); mast cell hyperplasia in bronchial smooth muscle and mucus glands occurs in asthmatic lungs (15)(16)(17); and mast cells are a rich source of proteases (18,19). Also, the acidic pH of the airways of asthma subjects (20) may promote ␤-tryptase proteolytic activity (21)(22)(23).…”