Mast Cell Proteases as Protective and Inflammatory Mediators

Abstract

Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by degranulating stimuli, which include cross-linking of high affinity IgE receptor FcεRI by IgE bound to multivalent allergen. Understanding and separating the functions of the proteases is important because expression differs among mast cells in different tissue locations. Differences between laboratory animals and humans in protease expression also influence the degree of confidence with which results obtained in animal models of mast cell function can be extrapolated to humans. The inflammatory potential of mast cell proteases was the first aspect of their biology to be explored and has received the most attention, in part because some of them—notably tryptases and chymases—are biomarkers of local and systemic mast cell degranulation and anaphylaxis. Although some of the proteases indeed augment allergic inflammation and are potential targets for inhibition to treat asthma and related allergic disorders, they are protective and even anti-inflammatory in some settings. For example, mast cell tryptases may protect from serious bacterial lung infections and may limit the “rubor” component of inflammation caused by vasodilating neuropeptides in the skin. Chymases help to maintain intestinal barrier function and to expel parasitic worms, and may support blood pressure during anaphylaxis by generating angiotensin II. In other life-or-death examples, carboxypeptidase A3 and other mast cell peptidases limit systemic toxicity of endogenous peptides like endothelin and neurotensin during septic peritonitis, and inactivate venom-associated peptides. On the other hand, mast cell peptidase-mediated destruction of protective cytokines, like IL-6, can enhance mortality from sepsis. Peptidases released from mast cells also influence non-mast cell proteases, such as by activating matrix metalloproteinase cascades, which are important in responses to infection and resolution of tissue injury. Overall, mast cell proteases have a variety of roles—inflammatory and anti-inflammatory, protective and deleterious—in keeping with the increasingly well-appreciated contributions of mast cells in allergy, tissue homeostasis, and innate immunity.

Proteomic Analysis of the SH2Domain-containing Leukocyte Protein of 76 kDa (SLP76) Interactome

“…They are stored in granules under a catalytically active form. They are released in the extracellular medium under physiological conditions during antigen-induced degranulation and they can have both pro-inflammatory effects in IgE-induced allergic inflammation, and anti-inflammatory effects in infection-associated inflammation (35). They can also be released under nonphysiological conditions, when granular membranes are solubilized by mild detergents during cell lysis.…”

IL-33/ST2 axis promotes mast cell survival via BCLXL

“…In chronic inflammation, MC could continue to "feed the fire" via ongoing mediator release, antigen presentation, or other mechanisms. Alternately, MC could help suppress disease, for instance by protease-mediated elimination of proinflammatory mediators, by facilitating tissue remodeling, or by promoting tolerance (61)(62)(63)(64). The effect of attenuating MC survival by blocking the IL-33/ST2 axis will be important to consider when evaluating IL-33 and ST2 as potential therapeutic targets.…”

Histologic and Histometric Examination of Spleen in Geese (Anser anser)

“…Except the histamine and heparin, mast cells release essential substances such as eosinophil chemotactic factor of anaphylaxis, which is the primary mediator of type I anaphylactic hypersensitivity, prostaglandin and slow reacting substance of anaphylaxis (Caughey, 2011). When these cells uptake the basic stains, they may be seen with different coloration as purple-red (metachromatic) (Jamur et al, 2005;Thangapandiyan and Balachandran, 2010).…”