Mast Cells Are Not Involved in the Development of Cyclosporin A-Induced Gingival Hyperplasia: A Study With Mast Cell-Deficient Mice

It is now well established that mast cells (MCs) play a crucial role in asthma. This is supported by multiple lines of evidence, including both clinical studies and studies on MC-deficient mice. However, there is still only limited knowledge of the exact effector mechanism(s) by which MCs influence asthma pathology. MCs contain large amounts of secretory granules, which are filled with a variety of bioactive compounds including histamine, cytokines, lysosomal hydrolases, serglycin proteoglycans and a number of MC-restricted proteases. When MCs are activated, e.g. in response to IgE receptor cross-linking, the contents of their granules are released to the exterior and can cause a massive inflammatory reaction. The MC-restricted proteases include tryptases, chymases and carboxypeptidase A3, and these are expressed and stored at remarkably high levels. There is now emerging evidence supporting a prominent role of these enzymes in the pathology of asthma. Interestingly, however, the role of the MC-restricted proteases is multifaceted, encompassing both protective and detrimental activities. Here, the current knowledge of how the MC-restricted proteases impact on asthma is reviewed.

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Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1

Journal of Neuroinflammation ◽

10.1186/s12974-020-01795-4 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Elín I. Magnúsdóttir ◽

Mirjana Grujic ◽

Jessica Bergman ◽

Gunnar Pejler ◽

Malin C. Lagerström

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Connective Tissue ◽

Treatment Options ◽

Cell Types ◽

Tissue Type ◽

Human Mast Cell ◽

Knock Out ◽

Endothelin 1 ◽

Deficient Mice

Abstract Background Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETARs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch. Methods In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed. Results CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect. Conclusion Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1.

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Neutrophil serine protease 4 is required for mast cell-dependent vascular leakage

Communications Biology ◽

10.1038/s42003-020-01407-0 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Andrew P. AhYoung ◽

Sterling C. Eckard ◽

Alvin Gogineni ◽

Hongkang Xi ◽

S. Jack Lin ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Serine Protease ◽

Mouse Models ◽

Vascular Leakage ◽

Allergic Reactions ◽

Acute Arthritis ◽

Sustained Reduction ◽

Granule Morphology ◽

Deficient Mice

AbstractVascular leakage, or edema, is a serious complication of acute allergic reactions. Vascular leakage is triggered by the release of histamine and serotonin from granules within tissue-resident mast cells. Here, we show that expression of Neutrophil Serine Protease 4 (NSP4) during the early stages of mast cell development regulates mast cell-mediated vascular leakage. In myeloid precursors, the granulocyte–macrophage progenitors (GMPs), loss of NSP4 results in the decrease of cellular levels of histamine, serotonin and heparin/heparan sulfate. Mast cells that are derived from NSP4-deficient GMPs have abnormal secretory granule morphology and a sustained reduction in histamine and serotonin levels. Consequently, in passive cutaneous anaphylaxis and acute arthritis models, mast cell-mediated vascular leakage in the skin and joints is substantially reduced in NSP4-deficient mice. Our findings reveal that NSP4 is required for the proper storage of vasoactive amines in mast cell granules, which impacts mast cell-dependent vascular leakage in mouse models of immune complex-mediated diseases.

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The Role of Mast Cells, Basophils and Interleukin-3 (IL-3) in Immune Responses to Parasites: Studies with Mast Cell- and IL-3-Deficient Mice

Mast Cells and Basophils ◽

10.1016/b978-012473335-0/50030-1 ◽

2000 ◽

pp. 439-452 ◽

Cited By ~ 2

Author(s):

Chris S. Lantz ◽

Stephen J. Galli

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Immune Responses ◽

Interleukin 3 ◽

Deficient Mice

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Anticoagulantly active heparin-like molecules from mast cell-deficient mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.250.5.h879 ◽

1986 ◽

Vol 250 (5) ◽

pp. H879-H888 ◽

Cited By ~ 2

Author(s):

J. A. Marcum ◽

J. B. McKenney ◽

S. J. Galli ◽

R. W. Jackman ◽

R. D. Rosenberg

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Enzyme Inhibitor ◽

Biologically Active ◽

Time Interval ◽

Heparin Binding ◽

Similar Time ◽

A Minor ◽

Deficient Mice

To assess the contribution of mast cells to the maintenance of blood fluidity, the hindlimb vasculature of mast cell-deficient mice (W/Wv) and littermates containing normal levels of mast cells (+/+), were perfused with purified human thrombin and antithrombin. Enzyme-inhibitor complex generation within the vasculature was enhanced to a comparable extent for W/Wv and +/+ mice over the uncatalyzed rate, that level of complex produced within a similar time interval in the absence of heparin. Perfusion of purified Flavobacterium heparinase prior to infusion of the hemostatic components, or perfusion of antithrombin modified at the heparin-binding domain, reduced W/Wv and +/+ hindlimb thrombin-antithrombin complex formation to the uncatalyzed rate. To further define the cellular source of the vascular-associated heparin-like molecules, endothelial cells isolated from epididymal fat pads of W/Wv and +/+ mice were grown in vitro. The acceleration of thrombin-antithrombin interactions in the presence of endothelial cell-derived glycosaminoglycans was similar for W/Wv and +/+ mice, was abolished with purified bacterial heparinase, and was expressed to only a minor extent when utilizing modified antithrombin. The biologically active mucopolysaccharides appear to be present on the cell surface.

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Tissue‐dependent differences in the asynchronous appearance of mast cells in normal mice and in congenic mast cell‐deficient mice after infusion of normal bone marrow cells

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.1996.d01-610.x ◽

1996 ◽

Vol 103 (2) ◽

pp. 316-321 ◽

Cited By ~ 18

Author(s):

T. DU ◽

D. S. FRIEND ◽

K. F. AUSTEN ◽

H. R. KATZ

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Mast Cells ◽

Bone Marrow Cells ◽

Normal Bone Marrow ◽

Normal Bone ◽

Deficient Mice ◽

Marrow Cells

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Phenotypic changes of bone marrow-derived mast cells after intraperitoneal transfer into W/Wv mice that are genetically deficient in mast cells.

Journal of Experimental Medicine ◽

10.1084/jem.165.3.615 ◽

1987 ◽

Vol 165 (3) ◽

pp. 615-627 ◽

Cited By ~ 63

Author(s):

K Otsu ◽

T Nakano ◽

Y Kanakura ◽

H Asai ◽

H R Katz ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Mast Cells ◽

Adoptive Transfer ◽

Gel Filtration ◽

Chondroitinase Abc ◽

Indirect Immunofluorescence Staining ◽

Deficient Mice

The ability of mouse IL-3-dependent, bone marrow culture-derived mast cells (BMMC) to generate serosal mast cells (SMC) in vivo after adoptive transfer to mast cell-deficient mice has been defined by chemical and immunochemical criteria. BMMC differentiated and grown from WBB6F1-+/+ mouse progenitor cells in medium containing PWM/splenocyte-conditioned medium synthesized a approximately 350,000 Mr protease-resistant proteoglycan bearing approximately 55,000 Mr glycosaminoglycans, as defined by gel filtration of each. Approximately 85% of the glycosaminoglycans bound to the cell-associated BMMC proteoglycans were chondroitin sulfates based upon their susceptibility to chondroitinase ABC digestion; HPLC of the chondroitinase ABC-generated unsaturated disaccharides revealed these glycosaminoglycans to be chondroitin sulfate E. As determined by heparinase and nitrous acid degradations, approximately 10% of the glycosaminoglycans bound to BMMC proteoglycans were heparin. In contrast, mast cells recovered from the peritoneal cavity of congenitally mast cell-deficient WBB6F1-W/Wv mice 15 wk after intraperitoneal injection of BMMC synthesized approximately 650,000 Mr protease-resistant proteoglycans that contained approximately 80% heparin glycosaminoglycans of approximately 105,000 Mr. Thus, after adoptive transfer, the SMC of the previously mast cell-deficient mice were like those recovered from the normal WBB6F1-+/+ mice that were shown to synthesize approximately 600,000 Mr proteoglycans that contained approximately 80% heparin glycosaminoglycans of approximately 115,000 Mr. As assessed by indirect immunofluorescence staining and flow cytometry using the B1.1 rat mAb (an antibody that recognizes an epitope located on the neutral glycosphingolipid globopentaosylceramide), approximately 5% of BMMC bound the antibody detectably, whereas approximately 72% of the SMC that were harvested from mast cell-deficient mice 15 wk after adoptive transfer of BMMC were B1.1-positive; approximately 82% of SMC from WBB6F1-+/+ mice bound the antibody. These biochemical and immunochemical data are consistent with the results of previous adoptive transfer studies that characterized mast cells primarily on the basis of morphologic and histochemical criteria. Thus, IL-3-dependent BMMC developed in vitro, cells that resemble mucosal mast cells, can give rise in vivo to SMC that express phenotypic characteristics of connective tissue mast cells.

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Requirement of Gab2 for mast cell development and KitL/c-Kit signaling

Blood ◽

10.1182/blood.v99.5.1866 ◽

2002 ◽

Vol 99 (5) ◽

pp. 1866-1869 ◽

Cited By ~ 98

Author(s):

Keigo Nishida ◽

Lin Wang ◽

Eiichi Morii ◽

Sung Joo Park ◽

Masahiro Narimatsu ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Binding Sites ◽

Cell Development ◽

Pleckstrin Homology Domain ◽

Akt Activation ◽

Kit Ligand ◽

Adaptor Molecule ◽

Potential Binding ◽

Deficient Mice

Mast cells are thought to participate in a variety of immune responses, such as parasite resistance and the allergic reaction. Mast cell development depends on stem cell factor (Kit ligand) and its receptor, c-Kit. Gab2 is an adaptor molecule containing a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab2 is phosphorylated on tyrosine after stimulation with cytokines and growth factors, including KitL. Gab2-deficient mice were created to define the physiological requirement for Gab2 in KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, the number of mast cells was reduced markedly in the stomach and less severely in the skin. Bone marrow–derived mast cells (BMMCs) from the Gab2-deficient mice grew poorly in response to KitL. KitL-induced ERK MAP kinase and Akt activation were impaired in Gab2-deficient BMMCs. These data indicate that Gab2 is required for mast cell development and KitL/c-Kit signaling.

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Mast Cell-Dependent Control of Giardia lamblia Infections in Mice

Infection and Immunity ◽

10.1128/iai.72.11.6642-6649.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6642-6649 ◽

Cited By ~ 74

Author(s):

Erqiu Li ◽

Ping Zhou ◽

Ziva Petrin ◽

Steven M. Singer

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Response ◽

Giardia Lamblia ◽

Immunoglobulin A ◽

Serum Levels ◽

Protective Role ◽

Intestinal Helminth ◽

Cell Responses ◽

Deficient Mice

ABSTRACT Mast cells are important for protective immunity to intestinal helminth infections and as mediators of allergic disease. Their role in protozoan infections is less well described. We have therefore analyzed mast cell responses and parasite control in mice infected with the protozoan Giardia lamblia. We also measured immunoglobulin A (IgA) responses to the parasite, as IgA can have a protective role in this model. c-kitw/wv mice failed to make parasite-specific IgA, mount a mast cell response, or eliminate the infection. Anti-c-kit-treated C57BL/6 mice had normal IgA responses, lacked mast cell responses, had reduced interleukin-6 (IL-6) mRNA in the small intestine, and failed to control the infection within 10 days. IL-9-deficient mice had a significant but reduced mast cell response and still controlled the infection within 2 weeks. Interestingly, IL-6-deficient mice had enhanced mast cell responses yet failed to rapidly control the infection. However, prevention of mast cell responses in IL-6-deficient mice by anti-c-kit treatment did not lead to parasite elimination. Both IL-6- and IL-9-deficient mice had normal IgA production. IL-6-deficient mice had significant serum levels of mast cell mediators, histamine and mast cell protease 1, following infection. Together, these results show that mast cells are important for the rapid control of Giardia infections in mice. Furthermore, they show that IL-6 is not necessary for these mast cell responses. Instead, they suggest that mast cell production of IL-6 appears to be important for control of this infection.

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