Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability

Gautam, Narinder; Olofsson, A M; Herwald, Heiko; Iversen, Lars; Lundgren-Åkerlund, Evy; Hedqvist, Per; Arfors, K. E.; Flodgaard, Hans; Lindbom, Lennart

doi:10.1038/nm1001-1123

Cited by 312 publications

(335 citation statements)

References 29 publications

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“…Treatment of PMN with anti-CD18 mAb IB4 (3 g/ml, 30 min) before injection, which prevented PMN arrest on EC while rolling remained intact, markedly reduced HBP deposition. This observation emphasizes the importance of firm PMN adhesion to EC and signaling via ␤ 2 integrin in the release of HBP from PMN storage compartments (13).…”

Section: Neutrophil-derived Hbp Binds To Ecmentioning

confidence: 63%

“…In particular, constituents of neutrophil azurophilic granules including the members of the serprocidin family, such as cathepsin G and heparinbinding protein (HBP) 3 also known as cationic antimicrobial protein of molecular mass 37 kDa (CAP37/azurocidin), have attracted attention in this respect, and accordingly, have been suggested to serve as links between initial and delayed phases of cellular immune responses (11). In contrast to cathepsin G, HBP is not only localized in azurophilic granules but also in more readily mobilized compartments close to the plasma membrane (12) and can therefore be released rapidly upon neutrophil activation and adhesion (13). Once secreted, HBP carries out powerful monocyte-activating properties.…”

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confidence: 99%

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Neutrophil-Derived Heparin-Binding Protein (HBP/CAP37) Deposited on Endothelium Enhances Monocyte Arrest under Flow Conditions

Soehnlein

Xie²,

Ulbrich³

et al. 2005

The Journal of Immunology

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In acute inflammation, infiltration of neutrophils often precedes a second phase of monocyte invasion, and data in the literature suggest that neutrophils may directly stimulate mobilization of monocytes via neutrophil granule proteins. In this study, we present a role for neutrophil-derived heparin-binding protein (HBP) in monocyte arrest on endothelium. Adhesion of neutrophils to bovine aorta endothelial cells (ECs) or HUVEC-triggered secretion of HBP and binding of the protein to the EC surface. Blockade of neutrophil adhesion by treatment with a mAb to CD18 greatly reduced accumulation of HBP. In a flow chamber model, immobilized recombinant HBP induced arrest of human monocytes or monocytic Mono Mac 6 (MM6) cells to activated EC or plates coated with recombinant adhesion molecules (E-selectin, P-selectin, VCAM-1). However, immobilized recombinant HBP did not influence arrest of neutrophils or lymphocytes. Treatment of MM6 cells with recombinant HBP evoked a rapid and clear-cut increase in cytosolic free Ca2+ that was found to be critical for the HBP-induced monocyte arrest inasmuch as pretreatment with the intracellular calcium chelating agent BAPTA-AM abolished the evoked increase in adhesion. Thus, secretion of a neutrophil granule protein, accumulating on the EC surface and promoting arrest of monocytes, could contribute to the recruitment of monocytes at inflammatory loci.

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Section: Neutrophil-derived Hbp Binds To Ecmentioning

confidence: 63%

mentioning

confidence: 99%

Neutrophil-Derived Heparin-Binding Protein (HBP/CAP37) Deposited on Endothelium Enhances Monocyte Arrest under Flow Conditions

Soehnlein

Xie²,

Ulbrich³

et al. 2005

The Journal of Immunology

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“…Its location in rapidly mobilized secretory vesicles allows a rapid discharge upon PMN adhesion and activation. PMN-derived azurocidin could be demonstrated to provoke a rapid rise in cytosolic-free Ca 2ϩ in adjacent EC, formation of actin stress fibers, and increased paracellular permeability [67]. The responses to azurocidin stimulation are identical to those achieved by chemoattractant stimulation of PMN, and immunoneutralization of azurocidin in PMN-derived secretion inhibits the activity completely, substantiating the critical role of this protein in PMNevoked alterations in vascular permeability.…”

Section: Azurocidin Activates Ecmentioning

confidence: 74%

Neutrophil-derived azurocidin alarms the immune system

Soehnlein

Lindbom

2008

Journal of Leukocyte Biology

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Azurocidin (heparin-binding protein/ cationic antimicrobial protein of 37 kD) is a protein that is mobilized rapidly from emigrating polymorphonuclear leukocytes (PMN). Initially, this inactive serine protease was recognized for its antimicrobial effects. However, it soon became apparent that azurocidin may act to alarm the immune system in different ways and thus serve as an important mediator during the initiation of the immune response. Azurocidin, released from PMN secretory vesicles or primary granules, acts as a chemoattractant and activator of monocyte and macrophages. The functional consequence is enhancement of cytokine release and bacterial phagocytosis, allowing for a more efficient bacterial clearance. Leukocyte activation by azurocidin is mediated via ␤ 2 -integrins, and azurocidin-induced chemotaxis is dependent on formyl-peptide receptors. In addition, azurocidin activates endothelial cells leading to vascular leakage and edema formation. For these reasons, targeting azurocidin release and its actions may have therapeutic potential in inflammatory disease conditions. J. Leukoc. Biol. 85: 344 -351; 2009.

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“…It has also been reported to play a role in neutrophil-induced increase in vascular permeability (12). The mechanism for these functions is largely unknown.…”

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confidence: 99%

Basic Residues in Azurocidin/HBP Contribute to Both Heparin Binding and Antimicrobial Activity

McCabe

Cukierman

Gabay

2002

Journal of Biological Chemistry

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Azurocidin/CAP37/HBP is an antimicrobial and chemotactic protein that is part of the innate defenses of human neutrophils. In addition, azurocidin is an inactive serine protease homolog with binding sites for diverse ligands including heparin and the bovine pancreatic trypsin inhibitor (BPTI). The structure of the protein reveals a highly cationic domain concentrated on one side of the molecule and responsible for its strong polarity. To investigate the role of this highly basic region, we produced three recombinant azurocidin mutant proteins that were altered in either one or both of two clusters of 4 basic residues located symmetrically on each side of a central cleft in the cationic domain. Two of the mutant proteins (Loop 3: R5Q, K6Q, R8Q, and R10Q; Loop 4: R61Q, R62Q, R63Q, and R65Q) exhibited little or no change in heparin and BPTI binding or in antimicrobial function. In contrast, the Loop 3/Loop 4 mutant (R5Q, K6Q, R8Q, R10Q, R61Q, R62Q, R63Q, and R65Q) in which all 8 basic residues were replaced showed greatly decreased ability to bind heparin and to kill Escherichia coli and Candida albicans. Thus, we report that the 8 basic residues that were altered in the Loop 3/Loop 4 mutant contribute to the ability of the wild-type azurocidin molecule to bind heparin and to kill E. coli and C. albicans. Because BPTI binding was comparable in wild-type and Loop 3/Loop 4 mutant protein, we conclude that the same 8 basic residues are not involved in the binding of BPTI to azurocidin, supporting the notion that the binding site for BPTI is distinct from the site involved in heparin binding and antimicrobial activity. Finally, we show that removal of all 4 positively charged amino acids in the 20 -44 azurocidin sequence (DMC1: R23Q,H24S,H32S,R34Q), a region previously thought to contain an antimicrobial domain, does not affect the activity of the protein against E. coli, Streptococcus faecalis, and C. albicans.Azurocidin/CAP37/HBP is an antimicrobial and chemotactic protein (1-7) that forms part of the innate defenses of human neutrophils (8 -11). It has also been reported to play a role in neutrophil-induced increase in vascular permeability (12). The mechanism for these functions is largely unknown. Structurally, azurocidin belongs to the serprocidin family, a group of serine proteases with antimicrobial function but lacking enzymatic activity (13-16). Its three-dimensional structure has been elucidated and shows a highly cationic region made of 16 basic amino acid residues and located at one pole of the molecule (17,18). In addition to its high density of positive charges, the cationic region also contains potential heparin binding consensus sequences that are located in loop areas of azurocidin tertiary structure (4, 17).Several ligands have been shown to bind to azurocidin, including heparin and the serine protease inhibitor BPTI 1 (4,19). In this report, we show that heparin and BPTI bind to distinct regions of the molecule and that these two ligands differentially affect antimicrobial activity. Indeed, binding ...

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Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability

Cited by 312 publications

References 29 publications

Neutrophil-Derived Heparin-Binding Protein (HBP/CAP37) Deposited on Endothelium Enhances Monocyte Arrest under Flow Conditions

Neutrophil-Derived Heparin-Binding Protein (HBP/CAP37) Deposited on Endothelium Enhances Monocyte Arrest under Flow Conditions

Neutrophil-derived azurocidin alarms the immune system

Basic Residues in Azurocidin/HBP Contribute to Both Heparin Binding and Antimicrobial Activity

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