Mast cell peptidases: chameleons of innate immunity and host defense

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.

Figure 1.

Timeline of selected milestones in chymase and tryptase research.

Figure 2.

Angiotensin docked to human chymase. The decapeptide angiotensin I, which is the best known natural substrate of human chymase, was fitted to the extended substrate binding and active site of human chymase and rendered using AutoDock Vina (http://vina.scripps.edu/). The starting point for the chymase catalytic domain structure was crystal-based Protein Data Bank–deposited structure 1pjp (130), minus the bound inhibitor. The angiotensin amino terminus is at the top of the stick figure. The site of hydrolysis is at Phe⁸, whose phenyl side chain is seen buried in a hydrophobic slot in the catalytic domain.