7 results on '"Mocsai, Attila"'
Search Results
2. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.
- Author
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Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, Reichardt W, Karlsson FJ, Radhakrishnan SV, Hanke K, Schmitt-Graeff A, Freudenberg M, von Loewenich FD, Wolf P, Leonhardt F, Baxan N, Pfeifer D, Schmah O, Schönle A, Martin SF, Mertelsmann R, Duyster J, Finke J, Prinz M, Henneke P, Häcker H, Hildebrandt GC, Häcker G, and Zeiser R
- Subjects
- Animals, Busulfan, Cyclophosphamide, Flow Cytometry, Freund's Adjuvant, Graft vs Host Disease physiopathology, Histological Techniques, Ileum microbiology, Immunohistochemistry, Kaplan-Meier Estimate, Luciferases, Magnetic Resonance Imaging, Membrane Glycoproteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Microarray Analysis, NADPH Oxidase 2, NADPH Oxidases genetics, Peroxidase, Reactive Oxygen Species metabolism, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation adverse effects, Ileum immunology, Microbiota immunology, Neutrophils immunology
- Abstract
Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.
- Published
- 2014
- Full Text
- View/download PDF
3. PI3Kβ plays a critical role in neutrophil activation by immune complexes.
- Author
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Kulkarni S, Sitaru C, Jakus Z, Anderson KE, Damoulakis G, Davidson K, Hirose M, Juss J, Oxley D, Chessa TA, Ramadani F, Guillou H, Segonds-Pichon A, Fritsch A, Jarvis GE, Okkenhaug K, Ludwig R, Zillikens D, Mocsai A, Vanhaesebroeck B, Stephens LR, and Hawkins PT
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, Blotting, Western, CD2 Antigens genetics, CD2 Antigens metabolism, Class Ia Phosphatidylinositol 3-Kinase genetics, Enzyme Inhibitors pharmacology, Female, Flow Cytometry, Gene Rearrangement, B-Lymphocyte genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains metabolism, Immunoglobulin Joining Region genetics, Immunoglobulin Joining Region metabolism, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region metabolism, In Situ Hybridization, Fluorescence, Male, Mice, Mice, Knockout, Mice, Transgenic, Neutrophils metabolism, Phosphoinositide-3 Kinase Inhibitors, Reactive Oxygen Species metabolism, Receptors, IgG metabolism, Receptors, Leukotriene B4 metabolism, Signal Transduction drug effects, Signal Transduction immunology, Antigen-Antibody Complex immunology, Class Ia Phosphatidylinositol 3-Kinase metabolism, Neutrophil Activation immunology, Neutrophils immunology
- Abstract
Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcγRs). Here, we used genetic and pharmacological approaches to define a selective role for the β isoform of phosphoinositide 3-kinase (PI3Kβ) in FcγR-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3Kβ alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3Kβ and PI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kβ by immune complexes involved cooperation between FcγRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B₄. Coincident activation by a tyrosine kinase-coupled receptor (FcγR) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the β isoform of PI3K. PI3Kβ-deficient mice were highly protected in an FcγR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcγR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kβ and PI3Kδ resulted in near-complete protection in the latter case. These results define PI3Kβ as a potential therapeutic target in inflammatory disease.
- Published
- 2011
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4. A fundamental role of mAbp1 in neutrophils: impact on beta(2) integrin-mediated phagocytosis and adhesion in vivo.
- Author
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Schymeinsky J, Gerstl R, Mannigel I, Niedung K, Frommhold D, Panthel K, Heesemann J, Sixt M, Quast T, Kolanus W, Mocsai A, Wienands J, Sperandio M, and Walzog B
- Subjects
- Animals, Cell Adhesion physiology, Escherichia coli pathogenicity, HL-60 Cells, Humans, In Vitro Techniques, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins antagonists & inhibitors, Microfilament Proteins deficiency, Microfilament Proteins genetics, Phagocytosis physiology, Protein-Tyrosine Kinases deficiency, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, RNA Interference, Receptors, IgG metabolism, Salmonella typhimurium pathogenicity, Syk Kinase, src Homology Domains genetics, CD18 Antigens physiology, Microfilament Proteins physiology, Neutrophils physiology, src Homology Domains physiology
- Abstract
The mammalian actin-binding protein 1 (mAbp1, Hip-55, SH3P7) is phosphorylated by the nonreceptor tyrosine kinase Syk that has a fundamental effect for several beta(2) integrin (CD11/CD18)-mediated neutrophil functions. Live cell imaging showed a dynamic enrichment of enhanced green fluorescence protein-tagged mAbp1 at the phagocytic cup of neutrophil-like differentiated HL-60 cells during beta(2) integrin-mediated phagocytosis of serum-opsonized Escherichia coli. The genetic absence of Syk or its pharmacologic inhibition using piceatannol abrogated the proper localization of mAbp1 at the phagocytic cup. The genetic absence or down-regulation of mAbp1 using the RNA interference technique significantly compromised beta(2) integrin-mediated phagocytosis of serum-opsonized E coli or Salmonella typhimurium in vitro as well as clearance of S typhimurium infection in vivo. Moreover, the genetic absence of mAbp1 almost completely abrogated firm neutrophil adhesion under physiologic shear stress conditions in vitro as well as leukocyte adhesion and extravasation in inflamed cremaster muscle venules of mice treated with tumor-necrosis factor alpha. Functional analysis showed that the down-regulation of mAbp1 diminished the number of beta(2) integrin clusters in the high-affinity conformation under flow conditions. These unanticipated results define mAbp1 as a novel molecular player in integrin biology that is critical for phagocytosis and firm neutrophil adhesion under flow conditions.
- Published
- 2009
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5. SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils.
- Author
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Newbrough SA, Mocsai A, Clemens RA, Wu JN, Silverman MA, Singer AL, Lowell CA, and Koretzky GA
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Cell Membrane metabolism, Gene Targeting, Mice, Neutrophils ultrastructure, Phosphoproteins deficiency, Phosphoproteins genetics, Phosphorylation, Tyrosine metabolism, Integrins metabolism, Neutrophils metabolism, Phosphoproteins metabolism, Receptors, IgG metabolism, Signal Transduction physiology
- Abstract
While the contribution of intracellular adaptor proteins to lymphocyte activation has been well studied, the function of these molecules in innate immune effector cells such as neutrophils has not been extensively addressed. Here we demonstrate a critical role for the adaptor molecule SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) in FcgammaR and integrin signaling. Stimulation of these receptors induces tyrosine phosphorylation and cytoplasmic relocalization of SLP-76 in freshly isolated murine neutrophils. Neutrophils lacking SLP-76 demonstrate decreased FcgammaR-induced calcium flux and reactive oxygen intermediate (ROI) production in response to immune complex stimulation. More dramatically, SLP-76-/- neutrophils fail to produce ROI, spread, or activate critical downstream regulators in response to integrin ligation. These results provide genetic evidence for a critical role of SLP-76 in the regulation of neutrophil function.
- Published
- 2003
- Full Text
- View/download PDF
6. Role for plastin in host defense distinguishes integrin signaling from cell adhesion and spreading.
- Author
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Chen H, Mocsai A, Zhang H, Ding RX, Morisaki JH, White M, Rothfork JM, Heiser P, Colucci-Guyon E, Lowell CA, Gresham HD, Allen PM, and Brown EJ
- Subjects
- Animals, Cell Adhesion, Cell Movement, Enzyme Precursors physiology, Immunity, Innate, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Microfilament Proteins, Neutrophils physiology, Protein-Tyrosine Kinases physiology, Respiratory Burst, Staphylococcal Infections immunology, Syk Kinase, CD18 Antigens physiology, Neutrophils immunology, Phosphoproteins physiology, Signal Transduction physiology
- Abstract
Integrin ligation activates both cell adhesion and signal transduction, in part through reorganization of the actin cytoskeleton. Plastins (also known as fimbrins) are actin-crosslinking proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. Here we show that plastin-deficient polymorphonuclear neutrophils (PMN) are deficient in killing the bacterial pathogen Staphylococcus aureus in vivo and in vitro, despite normal phagocytosis. Like integrin beta2-deficient PMN, plastin-deficient PMN cannot generate an adhesion-dependent respiratory burst, because of markedly diminished integrin-dependent syk activation. Unlike beta2(-/-) PMN, plastin-deficient PMN adhere and spread normally. Deficiency of plastin thus separates the classical integrin receptor functions of adhesion and spreading from intracellular signal transduction.
- Published
- 2003
- Full Text
- View/download PDF
7. The selective inhibition of the Syk tyrosine kinase ameliorates experimental autoimmune arthritis.
- Author
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Káposztás, Eszter, Balogh, Lili, Mocsai, Attila, Kemecsei, Éva, Jakus, Zoltán, and Németh, Tamás
- Subjects
EXPERIMENTAL arthritis ,PROTEIN-tyrosine kinases ,ANTIARTHRITIC agents ,JOINT pain ,B cell receptors ,DISEASE remission - Abstract
Autoimmune arthritis - such as rheumatoid arthritis - affect a significant proportion of the population, which can cause everyday joint pain, decreased mobility and reduced quality of life. Despite having more and more therapeutic options available, there are still a lot of patients who cannot reach remission or low disease activity by current therapies. This causes an urgent need for the development of new treatment options. The Syk tyrosine kinase plays an essential role in B cell receptor, Fc receptor and integrin signaling. It has been shown that the hematopoietic cell-specific deletion of Syk resulted in a complete protection against autoantibody-induced experimental arthritis. This prompted us to test the effect of entospletinib, a second generation, Syk-selective inhibitor, which has a tolerable safety profile according to hematological clinical trials, in experimental autoimmune arthritis. We found that entospletinib dosedependently decreased the macroscopic signs of joint inflammation, while it did not affect the health status of the animals. In line with these findings, local neutrophil accumulation and cytokine levels were reduced compared to the vehicle-treated group, while macrophage accumulation and synovial fibroblast numbers were not significantly altered. Meanwhile, entospletinib dosedependently decreased the cell responses of immune complex- or integrin ligand-activated neutrophils. Overall, we found that selective Syk inhibition by entospletinib reduced the activity of autoantibody-induced experimental arthritis, which seems to be based mainly on the effect of the inhibitor on neutrophil functions. Our data raise the possibility that entospletinib could be a good drug candidate in the treatment of human autoimmune arthritis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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