Mast cell proteases: multifaceted regulators of inflammatory disease

Abstract

IntroductionMast cells (MCs) are still mainly known for their harmful effects in connection with allergic reactions. However, this simplistic view is currently being extensively modified, and it is becoming more and more established that MCs have a complex array of functions and can contribute to a number of additional disorders. 1 In addition to being detrimental, MCs also carry out a number of beneficial functions, most notably in connection with innate immune responses toward various pathogens. 2 Moreover, recent studies indicate that MCs can play important roles in down-regulating adaptive immune responses. 3,4 As a consequence of this progress, MCs are gaining a massively increased interest worldwide, and much effort is invested into investigations of the mechanisms by which MCs contribute to different disorders.A striking morphologic feature of MCs is their abundance of electron-dense secretory granules, which contain large amounts of preformed compounds commonly referred to as "MC mediators." These include biogenic amines (histamine and serotonin), certain preformed cytokines (most notably tumor necrosis factor), serglycin proteoglycans, various lysosomal enzymes, and a number of MC-specific proteases of chymase, tryptase, or carboxypeptidase A (MC-CPA) type. [5][6][7][8] When MCs are induced to undergo degranulation, for example, through engagement of Fc⑀RI-bound IgE by polyvalent antigen, these mediators are thus released. 9 The MC proteases are expressed at exceptionally high levels, with mRNA levels approaching and even exceeding those of classic housekeeping genes, 10 and they are stored in remarkably high amounts. Indeed, it has been calculated that MC proteases may account for more than 25% of the total MC protein. 11,12 Importantly, in contrast to, for example, the pancreatic digestive proteases, the MC proteases are stored in fully active form; and when MCs undergo degranulation, large amounts of enzymatically active proteases are thus released into the extracellular space and probably have a profound impact on any condition in which MC degranulation occurs (Figure 1). Indeed, a plethora of potential functions of the MC proteases have previously been outlined, based on various approaches. 6 However, it is not until relatively recently that the in vivo functions of these enzymes have started to become unraveled through experimental approaches involving MC proteasedeficient mice. In this review, we summarize these findings and discuss their implications. Substrate specificity, distribution, and storageThe term "MC proteases" usually refers to the proteases that are expressed specifically by MCs and are stored in their secretory granules, that is, chymases, tryptases, and MC-CPA. However, it should be pointed out that MCs express a number of additional, non-MC-specific, proteases, such as lysosomal cathepsins, granzymes, neurolysin, and, possibly, cathepsin G. 6 Recently, the strictly MC-specific expression of the chymases has been used to generate mouse strains in which the Cre recombinase is expre...

Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells

“…Both proteases generate IL-33 mature forms with potent activity on ILC2s. Therefore, although mast cell proteases are differentially expressed in different mast cell subsets (42), all types of mast cells, including mucosal and connective tissue mast cells, may be able to generate highly active mature forms of IL-33. Mast cells are located close to IL-33-producing cells in tissues (33,34,39), and they interact very closely with ILC2s in vivo (26).…”

Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules

“…The role of mast cells in the self-defense system has been well established (31,32,40,41). For instance, mast cells sense the type 1 fimbriae of E. coli through surface-expressed CD48, resulting in release of the potent neutrophil chemoattractant TNF-a in a process that is pivotal for elimination of the bacteria (42).…”

Expressão e caracterização das quimases recombinantes específicas de mastócitos de camundongos (mMCP4 e 5)

“…Diferentemente, as quimases, triptases e carboxipeptidase A, denominadas mast cell proteases, são expressas somente por mastócitos e estocadas em seus grânulos. Os mastócitos também sintetizam e secretam outras proteases, como as metaloproteases de matriz extracelular (MMPs), catepsina D, C e E. Os níveis de expressão de proteases específicas de mastócitos são muito altos e os níveis de mRNA são próximos ou até maiores do que os níveis de mRNA dos genes constitutivos clássicos (PEJLER et al, 2010). As proteases específicas de mastócitos estocadas nos seus grânulos secretores somam cerca de 25% do conteúdo total de proteínas de mastócitos.…”

“…As proteases ativas são estocadas nos grânulos de mastócitos. Fonte: Pejler et al, 2010. As proteases específicas de mastócitos estão relacionadas com artrite, inflamação alérgica das vias aéreas, angiogênese tumoral, formação de aneurisma aórtico abdominal e glomerulonefrite e na defesa contra bactérias e parasitas MCNEIL et al, 2008;WAERN et al, 2009;SCANDIUZZI et al, 2010;SOUZA-JUNIOR et al, 2012). As proteases também possuem um papel modulador nas reações alérgicas, onde a β-triptase liberada durante a ativação dos mastócitos cliva a molécula de IgE limitando a inflamação alérgica (RAUTER et al, 2008).…”

“…A capacidade dos mastócitos em produzir e liberar uma variedade de mediadores químicos está relacionada com a fisiopatologia de reações alérgicas e de processos inflamatórios (PEJLER et al, 2010).…”