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Niels Borregaard - One of the best experts on this subject based on the ideXlab platform.
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Proteome profiling of human Neutrophil Granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of Neutrophil precursors
Journal of Leukocyte Biology, 2013Co-Authors: Sara Rørvig, Ole Østergaard, Niels H H Heegaard, Niels BorregaardAbstract:Neutrophils are indispensable in the innate immune defense against invading microorganisms. Neutrophils contain SVs and several subsets of Granules that are essential for their function. Proteins present in Neutrophil SVs and Granules are synthesized during terminal granulopoiesis in the bone marrow. The heterogeneity of Granules, as determined by marker proteins characteristic of each Granule subset, is thought to result from differences in the biosynthetic windows of major classes of Granule proteins, a process referred to as targeting by timing. Qualitative proteomic analysis of Neutrophil Granules, SVs, and plasma membrane has been performed before. Here, we performed subcellular fractionation on freshly isolated human Neutrophils by nitrogen cavitation and density centrifugation on a four-layer Percoll gradient. Granule subsets were pooled and subjected to SDS-PAGE, and gel pieces were in-gel-digested with trypsin. The resulting peptides were analyzed using LTQ Orbitrap XL tandem MS. A total of 1292 unique proteins were identified and grouped, according to the Neutrophil fraction, in which they displayed maximal expression. In addition to various known Neutrophil proteins, several uncharacterized proteins were found, as well as proteins not described previously in Neutrophils. To study the correlation between mRNA expression in Neutrophil precursors and the localization of their cognate proteins, the distribution of 126 identified proteins was compared with their mRNA expression profiles. The Neutrophil subcellular proteome profiles presented here may be used as a database in combination with the mRNA array database to predict and test the presence and localization of proteins in Neutrophil Granules and membranes.
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Granules Neutrophil elastase depends on serglycin proteoglycan for localization in
2013Co-Authors: Niels Borregaard, Carsten Utoft Niemann, Magnus Åbrink, Gunnar Pejler, Rikke L. Fischer, Erik Ilsø ChristensenAbstract:Abstract: Granule proteins play a major role in bacterial killing by Neutrophils. Serglycin proteoglycan, the major intracellular proteoglycan of hematopoietic cells, has been proposed to play a role in sorting and packing of Granule proteins. We examined the content of major Neutrophil Granule proteins in serglycin knock-out mice and found Neutrophil elastase absent from mature Neutrophils as shown by activity assay, Western blotting, and immunocytochemistry, whereas Neutrophil elastase mRNA was present. The localization of other Neutrophil Granule proteins did not differ between wild type and serglycin knock-out mice. Differential counts and Neutrophil ultrastructure were unaffected by the lack of serglycin, indicating that defective localization of Neutrophil elastase does not induce neutropenia itself, albeit mutations in the Neutrophil elastase gene can cause severe congenital neutropenia or cyclic neutropenia. The virulence of intraperitoneally injected Gram-negative bacteria ( Klebsiella pneumoniae
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Neutrophil elastase depends on serglycin proteoglycan for localization in Granules
Blood, 2007Co-Authors: Carsten Utoft Niemann, Magnus Åbrink, Gunnar Pejler, Rikke L. Fischer, Erik Ilsø Christensen, Stefan D. Knight, Niels BorregaardAbstract:Granule proteins play a major role in bacterial killing by Neutrophils. Serglycin proteoglycan, the major intracellular proteoglycan of hematopoietic cells, has been proposed to play a role in sorting and packing of Granule proteins. We examined the content of major Neutrophil Granule proteins in serglycin knockout mice and found Neutrophil elastase absent from mature Neutrophils as shown by activity assay, Western blotting, and immunocytochemistry, whereas Neutrophil elastase mRNA was present. The localization of other Neutrophil Granule proteins did not differ between wild-type and serglycin knockout mice. Differential counts and Neutrophil ultrastructure were unaffected by the lack of serglycin, indicating that defective localization of Neutrophil elastase does not induce neutropenia itself, albeit mutations in the Neutrophil elastase gene can cause severe congenital neutropenia or cyclic neutropenia. The virulence of intraperitoneally injected Gram-negative bacteria (Klebsiella pneumoniae) was increased in serglycin knockout mice compared with wild-type mice, as previously reported for Neutrophil elastase knockout mice. Thus, serglycin proteoglycan has an important role in localizing Neutrophil elastase in azurophil Granules of Neutrophils, while localization of other Granule proteins must be mediated by other mechanisms.
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the Neutrophil lipocalin ngal is a bacteriostatic agent that interferes with siderophore mediated iron acquisition
Molecular Cell, 2002Co-Authors: David H Goetz, Martin E Bluhm, Margaret A Holmes, Niels Borregaard, Kenneth N. Raymond, Roland K. StrongAbstract:Abstract First identified as a Neutrophil Granule component, Neutrophil gelatinase-associated lipocalin (NGAL; also called human Neutrophil lipocalin, 24p3, uterocalin, or neu -related lipocalin) is a member of the lipocalin family of binding proteins. Putative NGAL ligands, including Neutrophil chemotactic agents such as N-formylated tripeptides, have all been refuted by recent biochemical and structural results. NGAL has subsequently been implicated in diverse cellular processes, but without a characterized ligand, the molecular basis of these functions remained mysterious. Here we report that NGAL tightly binds bacterial catecholate-type ferric siderophores through a cyclically permuted, hybrid electrostatic/cation-π interaction and is a potent bacteriostatic agent in iron-limiting conditions. We therefore propose that NGAL participates in the antibacterial iron depletion strategy of the innate immune system.
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Regulation of human Neutrophil Granule protein expression.
Current opinion in hematology, 2001Co-Authors: Niels Borregaard, Kim Theilgaard-mönch, Ole E. Sørensen, Jack B. CowlandAbstract:The function of the mature polymorphonuclear Neutrophil is dependent on its Granules, each with its characteristic content of proteins. The Granule proteins are formed at different stages during maturation of Neutrophils from myeloblasts to segmented cells. The regulation of Granule protein expression is controlled by a number of transcription factors, many of which are also essential for commitment of multipotent hematopoietic stem cells to lineage-committed myeloid progenitor cells and for differentiation of these progenitor cells; among these, PU.1 and C/EBPalpha stand out as critical for all Granule proteins whereas AML-1 is critical for primary Granule protein expression and C/EBPepsilon for secondary and tertiary Granule protein expression.
James W. Larrick - One of the best experts on this subject based on the ideXlab platform.
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Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes.
Journal of immunology (Baltimore Md. : 1950), 1991Co-Authors: J G Morgan, H A Pereira, T Sukiennicki, John K. Spitznagel, M E Guerra, James W. LarrickAbstract:Human cationic antimicrobial protein (CAP37) is a Neutrophil Granule protein with monocyte chemotactic and antibacterial activity. A CAP37 cDNA clone of 899 bp was isolated from an HL-60 cDNA library using degenerate oligonucleotide probes based on partial N-terminal sequence of the CAP37 protein. The cDNA sequence predicts an open reading frame of 753 bp encoding a protein of 251 amino acids. A 26-residue eukaryotic signal peptide and a potential 7 amino acid pro-peptide are present at the N-terminus of the protein. The cDNA sequence also predicts three N-linked glycosylation attachment sites and eight intramolecular cysteines. The deduced amino acid sequence of CAP37 shows 44, 42, and 32% homology at the amino acid level to Neutrophil elastase, myeloblastin, and cathepsin G, respectively, suggesting that CAP37 is a member of the serine protease gene family. CAP37 does not possess serine protease activity probably due to mutations in two of three residues in the catalytic triad of the "charge relay system." Whereas CAP37 is expressed in undifferentiated HL-60 cells no message is detected in mature Neutrophils.
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cloning of the cdna for the serine protease homolog cap37 azurocidin a microbicidal and chemotactic protein from human granulocytes
Journal of Immunology, 1991Co-Authors: J G Morgan, H A Pereira, T Sukiennicki, John K. Spitznagel, M E Guerra, James W. LarrickAbstract:Human cationic antimicrobial protein (CAP37) is a Neutrophil Granule protein with monocyte chemotactic and antibacterial activity. A CAP37 cDNA clone of 899 bp was isolated from an HL-60 cDNA library using degenerate oligonucleotide probes based on partial N-terminal sequence of the CAP37 protein. The cDNA sequence predicts an open reading frame of 753 bp encoding a protein of 251 amino acids. A 26-residue eukaryotic signal peptide and a potential 7 amino acid pro-peptide are present at the N-terminus of the protein. The cDNA sequence also predicts three N-linked glycosylation attachment sites and eight intramolecular cysteines. The deduced amino acid sequence of CAP37 shows 44, 42, and 32% homology at the amino acid level to Neutrophil elastase, myeloblastin, and cathepsin G, respectively, suggesting that CAP37 is a member of the serine protease gene family. CAP37 does not possess serine protease activity probably due to mutations in two of three residues in the catalytic triad of the "charge relay system." Whereas CAP37 is expressed in undifferentiated HL-60 cells no message is detected in mature Neutrophils.
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human Neutrophil Granule cationic protein cap37 is a specific macrophage chemotaxin that shares homology with inflammatory proteinases
Advances in Experimental Medicine and Biology, 1991Co-Authors: John G Morgan, T Sukiennicki, John K. Spitznagel, Anne H Pereira, James W. LarrickAbstract:Cationic antimicrobial protein CAP37 (Mr = 37 kD) is derived from the azurophilic Granules of human PMN. In vitro and in vivo studies demonstrate that CAP37 is a novel monocyte-specific chemoattractant. The N-terminal amino acid sequence of CAP37 shares significant homology with a number of inflammatory molecules with protease activity including elastase and cathepsin G. However, substitutions in the catalytic triad (serine for a histidine at position 41 and glycine for a serine at position 175), may account for its lack of serine protease activity. A full length cDNA for CAP37 was identified in an HL60 cDNA library screened with oligonucleotide probes designed from the N-terminal amino acid sequence. Sequencing of the cDNA reveals a protein of 225 amino acids with significant nucleotide homology to cathepsin G and human Neutrophil elastase.
Yasushi Okamura - One of the best experts on this subject based on the ideXlab platform.
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the voltage gated proton channel hv1 vsop inhibits Neutrophil Granule release
Journal of Leukocyte Biology, 2016Co-Authors: Yoshifumi Okochi, Yasuaki Aratani, Hibret A. Adissu, Nana Miyawaki, Mari Sasaki, Kazuo Suzuki, Yasushi OkamuraAbstract:Neutrophil Granule exocytosis is crucial for host defense and inflammation. Neutrophils contain 4 types of Granules, the exocytotic release of which is differentially regulated. This exocytosis is known to be driven by diverse mediators, including calcium and nucleotides, but the precise molecular mechanism remains largely unknown. We show in the present study that voltage-gated proton (Hv) channels are necessary for the proper release of azurophilic Granules in Neutrophils. On activation of NADPH oxidase by PMA and IgG, Neutrophils derived from Hvcn1 gene knockout mouse exhibited greater secretion of MPO and elastase than WT cells. In contrast, release of LTF enriched in specific Granules was not enhanced in these cells. The excess release of azurophilic Granules in Hv1/VSOP-deficient Neutrophils was suppressed by inhibiting NADPH oxidase activity and, in part, by valinomycin, a potassium ionophore. In addition, Hv1/VSOP-deficient mice exhibited more severe lung inflammation after intranasal Candida albicans infection than WT mice. These findings suggest that the Hv channel acts to specifically dampen the release of azurophilic Granules through, in part, the suppression of increased positive charges at the plasma membrane accompanied by the activation of NADPH oxidase in Neutrophils.
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The voltage-gated proton channel Hv1/VSOP inhibits Neutrophil Granule release
Journal of leukocyte biology, 2015Co-Authors: Yoshifumi Okochi, Yasuaki Aratani, Hibret A. Adissu, Nana Miyawaki, Mari Sasaki, Kazuo Suzuki, Yasushi OkamuraAbstract:Neutrophil Granule exocytosis is crucial for host defense and inflammation. Neutrophils contain 4 types of Granules, the exocytotic release of which is differentially regulated. This exocytosis is known to be driven by diverse mediators, including calcium and nucleotides, but the precise molecular mechanism remains largely unknown. We show in the present study that voltage-gated proton (Hv) channels are necessary for the proper release of azurophilic Granules in Neutrophils. On activation of NADPH oxidase by PMA and IgG, Neutrophils derived from Hvcn1 gene knockout mouse exhibited greater secretion of MPO and elastase than WT cells. In contrast, release of LTF enriched in specific Granules was not enhanced in these cells. The excess release of azurophilic Granules in Hv1/VSOP-deficient Neutrophils was suppressed by inhibiting NADPH oxidase activity and, in part, by valinomycin, a potassium ionophore. In addition, Hv1/VSOP-deficient mice exhibited more severe lung inflammation after intranasal Candida albicans infection than WT mice. These findings suggest that the Hv channel acts to specifically dampen the release of azurophilic Granules through, in part, the suppression of increased positive charges at the plasma membrane accompanied by the activation of NADPH oxidase in Neutrophils.
Kenneth R. Mcleish - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic targeting of Neutrophil exocytosis.
Journal of Leukocyte Biology, 2020Co-Authors: Sergio D. Catz, Kenneth R. McleishAbstract:Dysregulation of Neutrophil activation causes disease in humans. Neither global inhibition of Neutrophil functions nor Neutrophil depletion provides safe and/or effective therapeutic approaches. The role of Neutrophil Granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes Neutrophil Granule formation and contents, the role Granule cargo plays in Neutrophil functional responses and Neutrophil-mediated diseases, and the mechanisms of Granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of Granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of Neutrophil exocytosis is a viable therapeutic strategy.
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Frontline Science: Tumor necrosis factor-α stimulation and priming of human Neutrophil Granule exocytosis.
Journal of leukocyte biology, 2017Co-Authors: Kenneth R. Mcleish, Michael L. Merchant, T. Michael Creed, Shweta Tandon, Michelle T. Barati, Silvia M. Uriarte, Richard A. WardAbstract:Neutrophil Granule exocytosis plays an important role in innate and adaptive immune responses. The present study examined TNF-α stimulation or priming of exocytosis of the 4 Neutrophil Granule subsets. TNF-α stimulated exocytosis of secretory vesicles and gelatinase Granules and primed specific and azurophilic Granule exocytosis to fMLF stimulation. Both stimulation and priming of exocytosis by TNF-α were dependent on p38 MAPK activity. Bioinformatic analysis of 1115 Neutrophil proteins identified by mass spectrometry as being phosphorylated by TNF-α exposure found that actin cytoskeleton regulation was a major biologic function. A role for p38 MAPK regulation of the actin cytoskeleton was confirmed experimentally. Thirteen phosphoproteins regulated secretory vesicle quantity, formation, or release, 4 of which-Raf1, myristoylated alanine-rich protein kinase C (PKC) substrate (MARCKS), Abelson murine leukemia interactor 1 (ABI1), and myosin VI-were targets of the p38 MAPK pathway. Pharmacologic inhibition of Raf1 reduced stimulated exocytosis of gelatinase Granules and priming of specific Granule exocytosis. We conclude that differential regulation of exocytosis by TNF-α involves the actin cytoskeleton and is a necessary component for priming of the 2 major Neutrophil antimicrobial defense mechanisms: oxygen radical generation and release of toxic Granule contents.
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A novel mechanism for enhanced Neutrophil recruitment, retention, and podocyte damage in immune complex-mediated glomerular disease.
Journal of Immunology, 2016Co-Authors: David W. Powell, Kenneth R. Mcleish, Min Tan, Ryan M. Sheehan, Shirong Zheng, Dawn J. Caster, Erik A. KorteAbstract:Glomerulonephritis (GN) is characterized by immune complex deposition and ensuing inflammation within the glomerulus of the kidney. Frank J. Dixon, a pioneer in immunologic kidney disease research, reported in 1965 that injection of nephrotoxic antibodies in rats and rabbits resulted in proteinuria and glomerular accumulation of Neutrophils, and that depletion of circulating Neutrophils reduced this immune-mediated glomerular damage and proteinuria. In the decades since, studies have confirmed a role for glomerular Neutrophil accumulation in human GN, but the mechanisms for Neutrophil recruitment and Neutrophil-directed injury have not been resolved. We previously reported genetic variants for a NF-κB inhibitor ABIN1 as risks for GN. Others also report that glomerular ABIN1 gene expression is altered in GN in mice and humans. Here we present that transgenic disruption of ABIN1 function results in exacerbated podocyte injury, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of Neutrophils in a mouse model of acute antibody-mediated GN. Moreover, a novel inhibitor of Neutrophil Granule release (SNAP23 peptide) also attenuates podocyte injury in this model. These in vivo findings are supported by in vitro experiments showing that secretome from homologous ABIN1 mutant podocytes activates Neutrophil chemotaxis and Granule release and Neutrophil Granule contents specifically disrupts cytoskeletal organization of ABIN1 mutant podocytes. These studies unfold a role for ABIN1 dysfunction in a novel Neutrophil-mediated mechanism of podocyte injury in GN and presents inhibition of Neutrophil Granule release as a promising novel therapeutic direction for kidney inflammation.
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exocytosis of Neutrophil Granule subsets and activation of prolyl isomerase 1 are required for respiratory burst priming
Journal of Innate Immunity, 2013Co-Authors: Kenneth R. Mcleish, Shweta Tandon, Silvia M. Uriarte, Timothy M Creed, Richard A. WardAbstract:This study tested the hypothesis that priming the Neutrophil respiratory burst requires both Granule exocytosis and activation of the prolyl isomerase Pin1. Fusion proteins containing the TAT cell permeability sequence and either the SNARE domain of syntaxin-4 or the N-terminal SNARE domain of SNAP-23 were used to examine the role of Granule subsets in TNF-mediated respiratory burst priming using human Neutrophils. Concentration-inhibition curves for exocytosis of individual Granule subsets and for priming of fMLF-stimulated superoxide release and phagocytosis-stimulated H2O2 production were generated. Maximal inhibition of priming ranged from 72 to 88%. Linear regression lines for inhibition of priming versus inhibition of exocytosis did not differ from the line of identity for secretory vesicles and gelatinase Granules, while the slopes or the y-intercepts were different from the line of identity for specific and azurophilic Granules. Inhibition of Pin1 reduced priming by 56%, while exocytosis of secretory vesicles and specific Granules was not affected. These findings indicate that exocytosis of secretory vesicles and gelatinase Granules and activation of Pin1 are independent events required for TNF-mediated priming of Neutrophil respiratory burst.
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The actin cytoskeleton regulates exocytosis of all Neutrophil Granule subsets
American journal of physiology. Cell physiology, 2007Co-Authors: Neelakshi R. Jog, Madhavi J. Rane, George Lominadze, Greg Luerman, Richard A. Ward, Kenneth R. McleishAbstract:A comprehensive analysis of the role of the actin cytoskeleton in exocytosis of the four different Neutrophil Granule subsets had not been performed previously. Immunoblot analysis showed that, com...
John K. Spitznagel - One of the best experts on this subject based on the ideXlab platform.
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synthetic bactericidal peptide based on cap37 a 37 kda human Neutrophil Granule associated cationic antimicrobial protein chemotactic for monocytes
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: H A Pereira, Jan Pohl, I Erdem, John K. SpitznagelAbstract:Abstract CAP37 (cationic antimicrobial protein of molecular mass 37 kDa) is a multifunctional protein isolated from the Granules of human Neutrophils. It is antibiotic and chemotactic and binds lipopolysaccharide. A synthetic peptide, amino acid sequence NQGRHFCGGALIHARFVMTAASCFQ, based on residues 20-44 of CAP37 protein mimics its antibiotic and lipopolysaccharide binding action. Peptide 20-44, at the concentrations tested, has antibacterial activity against Salmonella typhimurium, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus. The bactericidal action of the peptide was pH dependent, with maximum activity at pH 5.0 and pH 5.5 and decreased activity at pH 7.0. Various truncations, substitutions, and other modifications in the sequence deteriorate its activity. Free sulfhydryl groups and/or disulfide bridge formation are required for optimum antibiotic activity, since substitution of serines for, or alkylation of, cysteine residues 26 and 42 eliminates bactericidal activity. Evidently amino acids 20-44 represent an important, perhaps principal, antibacterial domain of CAP37. This peptide should provide new insight into the mechanism of antimicrobial activity of CAP37 and may serve as a model for new, useful, synthetic antibiotics.
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Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes.
Journal of immunology (Baltimore Md. : 1950), 1991Co-Authors: J G Morgan, H A Pereira, T Sukiennicki, John K. Spitznagel, M E Guerra, James W. LarrickAbstract:Human cationic antimicrobial protein (CAP37) is a Neutrophil Granule protein with monocyte chemotactic and antibacterial activity. A CAP37 cDNA clone of 899 bp was isolated from an HL-60 cDNA library using degenerate oligonucleotide probes based on partial N-terminal sequence of the CAP37 protein. The cDNA sequence predicts an open reading frame of 753 bp encoding a protein of 251 amino acids. A 26-residue eukaryotic signal peptide and a potential 7 amino acid pro-peptide are present at the N-terminus of the protein. The cDNA sequence also predicts three N-linked glycosylation attachment sites and eight intramolecular cysteines. The deduced amino acid sequence of CAP37 shows 44, 42, and 32% homology at the amino acid level to Neutrophil elastase, myeloblastin, and cathepsin G, respectively, suggesting that CAP37 is a member of the serine protease gene family. CAP37 does not possess serine protease activity probably due to mutations in two of three residues in the catalytic triad of the "charge relay system." Whereas CAP37 is expressed in undifferentiated HL-60 cells no message is detected in mature Neutrophils.
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cloning of the cdna for the serine protease homolog cap37 azurocidin a microbicidal and chemotactic protein from human granulocytes
Journal of Immunology, 1991Co-Authors: J G Morgan, H A Pereira, T Sukiennicki, John K. Spitznagel, M E Guerra, James W. LarrickAbstract:Human cationic antimicrobial protein (CAP37) is a Neutrophil Granule protein with monocyte chemotactic and antibacterial activity. A CAP37 cDNA clone of 899 bp was isolated from an HL-60 cDNA library using degenerate oligonucleotide probes based on partial N-terminal sequence of the CAP37 protein. The cDNA sequence predicts an open reading frame of 753 bp encoding a protein of 251 amino acids. A 26-residue eukaryotic signal peptide and a potential 7 amino acid pro-peptide are present at the N-terminus of the protein. The cDNA sequence also predicts three N-linked glycosylation attachment sites and eight intramolecular cysteines. The deduced amino acid sequence of CAP37 shows 44, 42, and 32% homology at the amino acid level to Neutrophil elastase, myeloblastin, and cathepsin G, respectively, suggesting that CAP37 is a member of the serine protease gene family. CAP37 does not possess serine protease activity probably due to mutations in two of three residues in the catalytic triad of the "charge relay system." Whereas CAP37 is expressed in undifferentiated HL-60 cells no message is detected in mature Neutrophils.
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human Neutrophil Granule cationic protein cap37 is a specific macrophage chemotaxin that shares homology with inflammatory proteinases
Advances in Experimental Medicine and Biology, 1991Co-Authors: John G Morgan, T Sukiennicki, John K. Spitznagel, Anne H Pereira, James W. LarrickAbstract:Cationic antimicrobial protein CAP37 (Mr = 37 kD) is derived from the azurophilic Granules of human PMN. In vitro and in vivo studies demonstrate that CAP37 is a novel monocyte-specific chemoattractant. The N-terminal amino acid sequence of CAP37 shares significant homology with a number of inflammatory molecules with protease activity including elastase and cathepsin G. However, substitutions in the catalytic triad (serine for a histidine at position 41 and glycine for a serine at position 175), may account for its lack of serine protease activity. A full length cDNA for CAP37 was identified in an HL60 cDNA library screened with oligonucleotide probes designed from the N-terminal amino acid sequence. Sequencing of the cDNA reveals a protein of 225 amino acids with significant nucleotide homology to cathepsin G and human Neutrophil elastase.