Mast Cell Peptidases

Abstract

Mast cells make and secrete an abundance of peptidases, which are stored in such large amounts in granules that they comprise a high fraction of all cellular protein. Perhaps no other immune cell is so generously endowed with peptidases. For many years after the main peptidases were first described, they were best known as markers of degranulation, for they are released locally in response to mast cell stimulation and can be distributed systemically and detected in blood. The principal peptidases are tryptases, chymases, carboxypeptidase A3, and dipeptidylpeptidase I (cathepsin C). Numerous studies suggest that these enzymes are important and even critical for host defense and homeostasis. Endogenous and allergen or pathogen-associated targets have been identified. Belying the narrow notion of peptidases as proinflammatory, several of the peptidases limit inflammation and toxicity of endogenous peptides and venoms. The peptidases are interdependent, so that absence or inactivity of one enzyme can alter levels and activity of others. Mammalian mast cell peptidases--chymases and tryptases especially--vary remarkably in number, expression, biophysical properties, and specificity, perhaps because they hyper-evolved under pressure from the very pathogens they help to repel. Tryptase and chymase involvement in some pathologies stimulated development of therapeutic inhibitors for use in asthma, lung fibrosis, pulmonary hypertension, ulcerative colitis, and cardiovascular diseases. While animal studies support the potential for mast cell peptidase inhibitors to mitigate certain diseases, other studies, as in mice lacking selected peptidases, predict roles in defense against bacteria and parasites and that systemic inactivation may impair host defense.

Quantotypic Properties of QconCAT Peptides Targeting Bovine Host Response toStreptococcus uberis

“…23 The five acute phase proteins: A1AT, A2M, LTF, HP, and SAA3 are typically secreted in the range of μg/ml to mg/ml to body fluids as a primary response to e.g., pathogens and to cytokine signaling. 7,10,20 The proteins estimated to be present at μg/ml level in milk include CD14, 24 the calgranulins (CALGB and CALGC) secreted by neutrophils and macrophages, 25 cathepsin C (CATC) secreted from a variety of granulated immune cells, 26 and the immune regulatory galectins (LGALS1 and LGALS3). 27 The groups of very low abundant proteins include cytokines (IL1B, IL6, IL8, TNF-α), cytokine receptors (IL1RA, IL6R) and chemokines (CXCL1, CXCL3) which all are highly potent mediators of inflammation.…”

Mast cells: multitalented facilitators of protection against bacterial pathogens

“…Extracellular traps are also formed in murine MCs and HMC-1 during S. aureus infection; however, S. aureus can subvert the extracellular antimicrobial activity by internalizing and persisting within these MCs, which may lead to chronic infection [42]. Apart from cytokines, MCs also have several enzymes used in host defense, such as MCP-6, which are stored in the MC granules and released upon infection [38,43]. MCP-6-null mice cannot efficiently clear K. pneumoniae from their peritoneal cavities, suggesting a crucial role for MCP-6 in innate immunity [44].…”

Mast Cell Proteases as Protective and Inflammatory Mediators

“…On the other hand, inhibitors of human chymase and cathepsin G oppose development of airway hyper-responsiveness and early- and late-phase rises in airway resistance in Ascaris suum -sensitized sheep challenged with allergen, and, in mice exposed to tobacco smoke, reduce lung neutrophilia and production of neutrophil chemoattractant 79, 80 . Explanations for observed differences in conclusions drawn from genetic versus pharmacological models likely relate in part to differences between mammals in the degree of chymase (and cathepsin G) redundancy—along with variations in enzymological properties, inhibitor susceptibilities, and cell-selective expression within and between mammals (reviewed in 4 ).…”

“…Several recent reviews provide in-depth coverage of particulars of mast cell protease biochemistry, genetics and biological function 1–4 . The present chapter emphasizes mast cell protease function as it relates to host defense and its frequent by-product, inflammation.…”