Generation and characterization of alpha‐chymase‐Cre transgenic mice

Müsch, Werner; Wege, Anja K.; Männel, Daniela N.; Hehlgans, Thomas

doi:10.1002/dvg.20378

Cited by 40 publications

(29 citation statements)

References 10 publications

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“…A common approach has been to generate mice in which Cre recombinase (Cre) is expressed under the control of promoters thought to be “MC-specific” or at least “MC-associated” (Feyerabend et al, 2009; Lilla et al, 2011; Musch, Wege, Mannel, & Hehlgans, 2008; Scholten et al, 2008). To date, three new strains of mutant mice with marked constitutive deficiencies in MCs have been reported (Dudeck et al, 2011; Feyerabend et al, 2011; Lilla et al, 2011) (Table 1).…”

Section: Genetic Approaches For Analyzing the Functions Of Mast Cementioning

confidence: 99%

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Galli

Tsai

Marichal

et al. 2015

Advances in Immunology

102

110

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The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such “controversial” results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

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Section: Genetic Approaches For Analyzing the Functions Of Mast Cementioning

confidence: 99%

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Galli

Tsai

Marichal

et al. 2015

Advances in Immunology

102

110

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“…However, caution should be exercised in interpreting results in these mice, as they show other haematopoietic abnormalities, such as megakaryocytic and myeloid cell expansion, and cardiac aberrancies likely attributable to Corin disruption (Nigrovic et al, 2008). Recently, two novel transgenic mouse models have been generated that express the recombinase Cre under the control of a MC-specific promoter, such as MC Protease-5 (Scholten et al, 2008) or alpha-Chymase (Musch et al, 2008) promoters, which may be MC ablated if crossed with transgenic animals carrying a Cre-inducible diphtheria toxin receptor. These new mouse models may replace cKit mutants in many MC studies, but Kit W/WÀv and Kit WÀsh/WÀsh mice still represent valuable instruments for the identification of novel MC-unrelated c-Kit functions.…”

Section: C-kit and Mast Cells In Cancer P Pittoni Et Almentioning

confidence: 99%

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

et al. 2010

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c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumorcell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. Here, we summarize the tumor-intrinsic and -extrinsic roles of c-Kit in cancer and discuss TKIs with their on-and off-targets, with a special emphasis on MCs as paradigmatic c-Kit-dependent accomplices for tumor progression.

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“…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 expressed under the control of chymase promoters, strains that can be used to specifically inactivate genes of interest in MCs. 14,15 Of the 3 classes of MC proteases, the tryptases and chymases are serine proteases, whereas MC-CPA is a Zn-dependent metalloprotease. 6,16 Tryptases are denoted so because of their trypsin-like substrate specificity; that is, they cleave preferentially after Lys/ Arg residues (Table 1).…”

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confidence: 99%

Mast cell proteases: multifaceted regulators of inflammatory disease

Pejler

Rönnberg

Waern

et al. 2010

Blood

334

296

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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...

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Generation and characterization of alpha‐chymase‐Cre transgenic mice

Cited by 40 publications

References 10 publications

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

Mast cell proteases: multifaceted regulators of inflammatory disease

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