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  • Approaches for analyzing the roles of mast cells and their proteases in vivo. Advances in immunology Galli, S. J., Tsai, M., Marichal, T., Tchougounova, E., Reber, L. L., Pejler, G. 2015; 126: 45-127


    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.

    View details for DOI 10.1016/

    View details for PubMedID 25727288

  • Contribution of Mast Cell-Derived Interleukin-1 beta to Uric Acid Crystal-Induced Acute Arthritis in Mice ARTHRITIS & RHEUMATOLOGY Reber, L. L., Marichal, T., Sokolove, J., Starkl, P., Gaudenzio, N., Iwakura, Y., Karasuyama, H., Schwartz, L. B., Robinson, W. H., Tsai, M., Galli, S. J. 2014; 66 (10): 2881-2891

    View details for DOI 10.1002/art.38747

    View details for Web of Science ID 000342744300026

  • Targeting mast cells in inflammatory diseases PHARMACOLOGY & THERAPEUTICS Reber, L. L., Frossard, N. 2014; 142 (3): 416-435


    Although mast cells have long been known to play a critical role in anaphylaxis and other allergic diseases, they also participate in some innate immune responses and may even have some protective functions. Data from the study of mast cell-deficient mice have facilitated our understanding of some of the molecular mechanisms driving mast cell functions during both innate and adaptive immune responses. This review presents an overview of the biology of mast cells and their potential involvement in various inflammatory diseases. We then discuss some of the current pharmacological approaches used to target mast cells and their products in several diseases associated with mast cell activation.

    View details for DOI 10.1016/j.pharmthera.2014.01.004

    View details for Web of Science ID 000335612700009

    View details for PubMedID 24486828

  • Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4-Dependent Mechanism JOURNAL OF IMMUNOLOGY Reber, L. L., Daubeuf, F., Pejler, G., Abrink, M., Frossard, N. 2014; 192 (4): 1847-1854


    Mast cells (MCs) are found in large numbers in lungs of patients with pulmonary fibrosis. However, the functions of MCs in lung fibrosis remain largely unknown. We assessed the role of MCs and MC protease 4 (MCPT4), the mouse counterpart of human MC chymase, in a mouse model of bleomycin (BLM)-induced lung injury. We found that levels of inflammation in the bronchoalveolar lavage and the lung, as well as levels of lung fibrosis, were reduced 7 d after intranasal delivery of BLM MC-deficient Kit(W-sh/W-sh) mice compared with wild-type (WT) mice. Confirming the implication of MCs in these processes, we report that the levels of inflammation and fibrosis observed in Kit(W-sh/W-sh) mice can be restored to those observed in WT mice after the adoptive transfer of bone marrow-derived cultured MCs into Kit(W-sh/W-sh) mice. Additionally, we show that levels of inflammation and fibrosis are also reduced in MC chymase MCPT4-deficient mice as compared with WT mice at day 7, suggesting a role for MC-derived MCPT4 in these processes. Our results support the conclusion that MCs can contribute to the initial lung injury induced by BLM through release of the MCPT4 chymase.

    View details for DOI 10.4049/jimmunol.1300875

    View details for Web of Science ID 000331267200052

    View details for PubMedID 24453258

  • A Beneficial Role for Immunoglobulin E in Host Defense against Honeybee Venom IMMUNITY Marichal, T., Starkl, P., Reber, L. L., Kalesnikoff, J., Oettgen, H. C., Tsai, M., Metz, M., Galli, S. J. 2013; 39 (5): 963-975


    Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response that increased their resistance to subsequent challenge with potentially lethal amounts of the venom. Our data indicate that IgE antibodies and the high affinity IgE receptor, FcεRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances.

    View details for DOI 10.1016/j.immuni.2013.10.005

    View details for Web of Science ID 000330950600017

    View details for PubMedID 24210352

  • Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice. journal of allergy and clinical immunology Reber, L. L., Marichal, T., Mukai, K., Kita, Y., Tokuoka, S. M., Roers, A., Hartmann, K., Karasuyama, H., Nadeau, K. C., Tsai, M., Galli, S. J. 2013; 132 (4): 881-8 e1 11


    Studies with c-kit mutant mast cell (MC)-deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA). However, interpretation of data obtained by using such approaches is complicated because c-kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs.We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response.Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later.Peanut-challenged, MC-deficient Kit(W-sh/W-sh) mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin-mediated selective depletion of MCs or basophils in Mcpt5-Cre;iDTR and Mcpt8(DTR) mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non-c-kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1(fl/fl) mice had reduced but still significant responses to peanut.Inducible and selective ablation of MCs or basophils in non-c-kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit(W-sh/W-sh) mice might influence the responses of these mice in this PIA model.

    View details for DOI 10.1016/j.jaci.2013.06.008

    View details for PubMedID 23915716

  • Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Reber, L. L., Marichal, T., Mukai, K., Kita, Y., Tokuoka, S. M., Roers, A., Hartmann, K., Karasuyama, H., Nadeau, K. C., Tsai, M., Galli, S. J. 2013; 132 (4): 881-?
  • Role of MSKs in Regulating NF-kappaB Activation Landes Biosciences Reber, L. L., Haegeman, G. 2013
  • New models for analyzing mast cell functions in vivo TRENDS IN IMMUNOLOGY Reber, L. L., Marichal, T., Galli, S. J. 2012; 33 (12): 613-625


    In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency.

    View details for DOI 10.1016/

    View details for Web of Science ID 000312055700005

    View details for PubMedID 23127755

  • The AGC Kinase Inhibitor H89 Attenuates Airway Inflammation in Mouse Models of Asthma PLOS ONE Reber, L. L., Daubeuf, F. O., Nemska, S., Frossard, N. 2012; 7 (11)


    H89 is a potent inhibitor of Protein Kinase A (PKA) and Mitogen- and Stress-Activated protein Kinase 1 (MSK1) with some inhibitory activity on other members of the AGC kinase family. H89 has been extensively used in vitro but its anti-inflammatory potential in vivo has not been reported to date. To assess the anti-inflammatory properties of H89 in mouse models of asthma.Mice were sensitized intraperitoneally (i.p.) to ovalbumin (OVA) with or without alum, and challenged intranasally with OVA. H89 (10 mg/kg) or vehicle was given i.p. two hours before each OVA challenge. Airway hyperresponsiveness (AHR) was assessed by whole-body barometric plethysmography. Inflammation was assessed by the total and differential cell counts and IL-4 and IL-5 levels in bronchoalveolar lavage (BAL) fluid. Lung inflammation, mucus production and mast cell numbers were analyzed after histochemistry. We show that treatment with H89 reduces AHR, lung inflammation, mast cell numbers and mucus production. H89 also inhibits IL-4 and IL-5 production and infiltration of eosinophils, neutrophils and lymphocytes in BAL fluid.Taken together, our findings implicate that blockade of AGC kinases may have therapeutic potential for the treatment of allergic airway inflammation.

    View details for DOI 10.1371/journal.pone.0049512

    View details for Web of Science ID 000311929800025

    View details for PubMedID 23189147

  • A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma JOURNAL OF IMMUNOLOGY Reber, L. L., Daubeuf, F., Plantinga, M., De Cauwer, L., Gerlo, S., Waelput, W., Van Calenbergh, S., Tavernier, J., Haegeman, G., Lambrecht, B. N., Frossard, N., De Bosscher, K. 2012; 188 (7): 3478-3487


    The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-?B and its subsequent recruitment onto the I?B? promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.

    View details for DOI 10.4049/jimmunol.1004227

    View details for Web of Science ID 000302150300061

    View details for PubMedID 22393156

  • Ser276 Phosphorylation of NF-kappa B p65 by MSK1 Controls SCF Expression in Inflammation PLOS ONE Reber, L., Vermeulen, L., Haegeman, G., Frossard, N. 2009; 4 (2)


    Transcription of the mast cell growth factor SCF (stem cell factor) is upregulated in inflammatory conditions, and this is dependent upon NF-kappaB, as well as the MAP kinases p38 and ERK activation. We show here that the MAPK downstream nuclear kinase MSK1 induces NF-kappaB p65 Ser276 phosphorylation upon IL-1beta treatment, which was inhibited in cells transfected with a MSK1 kinase-dead (KD) mutant compared to the WT control. In addition, we show by ChIP experiments that MSK1 as well as MAPK inhibition abolishes binding of p65, of its coactivator CBP, and of MSK1 itself to the kappaB intronic enhancer site of the SCF gene. We show that interaction between NF-kappaB and CBP is prevented in cells transfected by a p65 S276C mutant. Finally, we demonstrate that both transfections of MSK1-KD and MSK1 siRNA -- but not the WT MSK1 or control siRNA -- downregulate the expression of SCF induced by IL-1ss. Our study provides therefore a direct link between MSK1-mediated phosphorylation of Ser276 p65 of NF-kappaB, allowing its binding to the SCF intronic enhancer, and pathophysiological SCF expression in inflammation.

    View details for DOI 10.1371/journal.pone.0004393

    View details for Web of Science ID 000265483700008

    View details for PubMedID 19197368

  • Stem cell factor and its receptor c-Kit as targets for inflammatory diseases EUROPEAN JOURNAL OF PHARMACOLOGY Reber, L., da Silva, C. A., Frossard, N. 2006; 533 (1-3): 327-340


    Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-gamma, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases.

    View details for DOI 10.1016/j.ejphar.2005.12.067

    View details for Web of Science ID 000236265400031

    View details for PubMedID 16483568

  • Stem cell factor expression, mast cells and inflammation in asthma FUNDAMENTAL & CLINICAL PHARMACOLOGY da Silva, C. A., Reber, L., Frossard, N. 2006; 20 (1): 21-39


    The Kit ligand SCF or stem cell factor (SCF) is a multipotent growth factor, acting as an important growth factor for human mast cells. SCF induces chemotaxis and survival of the mast cell, as well as proliferation and differentiation of immature mast cells from CD34(+) progenitors. Additionally, SCF enhances antigen-induced degranulation of human lung-derived mast cells, and induces a mast cell hyperplasia after subcutaneous administration. SCF expression increases in the airways of asthmatic patients, and this is reversed after treatment with glucocorticoids. A role for SCF may thus be hypothesized in diseases associated with a local increase in the number and/or activation of mast cells, as occurring in the airways in asthma. SCF will be reviewed as a potential therapeutic target in asthma, to control the regulation of mast cell number and activation. We here report the main pathways of SCF synthesis and signalling, and its potential role on airway function and asthma.

    View details for DOI 10.1111/j.1472-8206.2005.00390.x

    View details for Web of Science ID 000235042200003

    View details for PubMedID 16448392

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