Mast Cell-restricted Tryptases: Structure and Function in Inflammation and Pathogen Defense

Abstract

Mast cells (MCs) are highly specialized immune cells present in mammals and in lower organisms that predate the development of adaptive immunity. The strong evolutionary pressure to retain MCs for >500 million years suggests critical roles for these cells in our survival. In support of this conclusion, no human has been identified to date that lacks MCs, despite the adverse roles of MCs in systemic anaphylaxis and varied inflammatory disorders. MCs express numerous lineage-restricted neutral proteases, and four members of the chromosome 17A3.3 family of tryptases are preferentially expressed in mouse MCs. The anatomical location of MCs at host-environment interfaces has raised the possibility that some of these enzymes are evolutionally conserved because they are needed for combating infectious organisms. Here we review recent insights into the structure and function of MC tryptases in inflammation and host defense against bacteria and other infectious organisms. MC-restricted Granule Proteases and ProteoglycansA characteristic morphologic feature of mammalian mast cells (MCs) 3 is their electron-dense secretory granules, which contain serglycin proteoglycans (1, 2) bearing heparin (for review see Ref. 3) and chondroitin sulfates diB and E (4, 5). Heparin is the most negatively charged molecule in the body, and each rat and mouse peritoneal MC contains ϳ25 pg of this glycosaminoglycan, thereby explaining the avidity of MCs for cationic dyes (6). The repeating Ser-Gly sequence in serglycin where its glycosaminoglycans are attached cannot be cleaved by any known protease. This protease resistance feature is biologically relevant because the primary function of serglycin proteoglycans in MCs is to provide a scaffold for formation of macromolecular complexes with the cell's varied granule proteases. When properly folded, a positively charged face forms on the surface of each granule protease that allows it to bind tightly to the proteoglycan's negatively charged glycosaminoglycans (7-9).The proteases packaged in the secretory granules of mouse MCs include carboxypeptidase A3 (CPA3), granzyme B, cathepsin G, neuropsin, transmembrane tryptase/tryptase ␥/protease serine member S (Prss) 31, mouse MC protease (mMCP) 1-10, and mMCP-11/Prss34. Definitive evidence of the importance of heparin-containing serglycin proteoglycans in the packaging of specific cassettes of proteases in the MC's granules came with the characterization of N-deacetylase/Nsulfotransferase-2 (NDST-2)-null mice (10, 11). NDST-2 is essential for heparin biosynthesis and is preferentially expressed in MCs. Because of the loss of fully sulfated heparin, the MCs in the skin and peritoneal cavities of NDST-2-null mice store reduced amounts of mMCP-6 and almost no CPA3, mMCP-4, and mMCP-5, even though all four MC-restricted protease genes are transcribed at normal rates. The accumulated data led to the current view that serglycin proteoglycans are essential for the post-translational processing and granule accumulation of most, if not all, proteases stor...

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

“…If that mediator is selectively expressed by mast cells, and if its deletion does not significantly influence the expression of other mastcell products, then it is possible to draw conclusions about the role of that mast-cell product in vivo. For example, mice that lack mouse mast-cell protease-1 (mMCP-1) [26][27][28] , mMCP-4 29,30 , mMCP-6 [31][32][33] , or mouse mast cell-carboxypeptidase A (mMC-CPA) 34 , or that have a mutated mMC-CPA that essentially lacks enzymatic activity 11 , have been used to analyze whether the absence of these proteases (or their enzymatic activity) influences other aspects of the mast-cell phenotype, such as content of other stored mediators, as well as to define the functions of such mast-cell-associated proteases in vivo.…”

“…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.…”

Heparan Sulfate 6-O-Sulfotransferase Isoform-dependent Regulatory Effects of Heparin on the Activities of Various Proteases in Mast Cells and the Biosynthesis of 6-O-Sulfated Heparin

“…Each mast cell type is differentiated by the types of glycosaminoglycans and MC-specific proteases present and is involved in a variety of physiological and pathological processes (23)(24)(25)(26)(27)(28)(29)(30). CTMCs mainly produce heparin, whereas mucosal mast cells primarily produce highly sulfated chondroitin sulfate (23,31,32).…”

Genetic Inversion in Mast Cell-Deficient Wsh Mice Interrupts Corin and Manifests as Hematopoietic and Cardiac Aberrancy

“…Phylogenetic studies confirm that this lineage predates the development of humoral immunity, implying that participation in IgE-mediated responses is a rather late specialization. 1 Indeed, mast cells have now been implicated in a broad range of pathophysiologic processes, where they most typically initiate or amplify immune responses via rapid release of preformed and newly synthesized mediators. One important role in this regard is the mobilization of defenses against bacteria and parasites.…”