Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors

Abstract

Mast cells are now recognized as key players in diverse pathologies, but the mechanisms by which they contribute in such settings are only partially understood. Mast cells are packed with secretory granules, and when they undergo degranulation in response to activation the contents of the granules are expelled to the extracellular milieu. Chymases, neutral serine proteases, are the major constituents of the mast cell granules and are hence released in large amounts upon mast cell activation. Following their release, chymases can cleave one or several of a myriad of potential substrates, and the cleavage of many of these could potentially have a profound impact on the respective pathology. Indeed, chymases have recently been implicated in several pathological contexts, in particular through studies using chymase inhibitors and by the use of chymase-deficient animals. In many cases, chymase has been shown to account for mast cell-dependent detrimental effects in the respective conditions and is therefore emerging as a promising drug target. On the other hand, chymase has been shown to have protective roles in other pathological settings. More unexpectedly, chymase has also been shown to control certain homeostatic processes. Here, these findings are reviewed.

Mast Cell Chymase and Kidney Disease

“…Another important function of chymase may be its ability to enable tissue remodeling and fibrosis development either by directly activating proforms of enzymes such as MMP2 and MMP9, able to degrade extracellular matrix (ECM) proteins, or by directly degrading matrix proteins such as fibronectin and collagen IV, or by activating/generating profibrotic inflammatory products such as TGFβ and Ang II [ 11 ] ( Figure 1 ). While the role of chymase in local Ang II generation has been discussed in detail above, evidence has been provided that mMCP-4 can directly degrade ECM proteins.…”

“…Therefore, besides analyzing the chymase function through the use chymase-deficient mice, some in vivo studies have also employed chymase-specific inhibitors. Indeed, a whole series of selective chymase inhibitors have been developed for some decades, and their efficacy profile, selectivity over cathepsin G and action on non-human chymase have been recently summarized [ 11 ]. Since the initial description and use of chymase inhibitors to demonstrate the Ang II-forming activity in the human heart [ 99 ], many of the studies based on inhibitors have been performed in the context of heart disease [ 100 ].…”

“…Human chymase cleaves peptides after aromatic amino acids (Phe, Tyr, Trp and sometimes Leu) in a variety of both endogenous and exogenous peptides and protein targets, albeit not all of them have been confirmed in vivo [ 4 , 11 ]. Some of these targets could also play a role in renal inflammatory diseases.…”

“…There is also substantial evidence for its implication in the coagulation system, as it is capable to degrade thrombin and plasmin [ 28 , 29 , 30 ]. It also degrades proteins of the extracellular matrix, such as fibronectin [ 30 , 31 ], and a variety of other inflammatory proteins, including a select set of cytokines and adhesion receptors [ 10 , 11 , 32 ].…”

A Leak in the Dike

“…It has become evident that mast cell proteases play important roles in the immunobiology of mast cells and their roles in disease. In an intriguing review, Gunnar Pejler [13] provides an overview of the current understanding of mast cell chymase. Mucosal-associated invariant T (MAIT) cells are getting increasing attention as they produce proinflammatory cytokines in an innate-like manner and play an important role in controlling the host immune response [14].…”