CAP37, a neutrophil-derived multifunctional inflammatory mediator

Pereira, H. Anne

doi:10.1002/jlb.57.6.805

Cited by 91 publications

(59 citation statements)

References 70 publications

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“…Our investigations demonstrated that HBP is more readily mobilized than elastase, a protein closely related to HBP and known to be a component of azurophilic granules. 5 This finding is in line with reports from Pereira et al, 11,17 who found a massive release of HBP from neutrophils phagocytosing Staphylococcus aureus, whereas only minor amounts of CAP57 (cationic antimicrobial protein of molecular mass 57 kd also known as BPI (bactericidal permeability increasing protein) was secreted, which is stored in azurophilic granules. In Pereira et al's 17 study, however, no characterization of the compartments that contain HBP was performed.…”

Section: Discussionsupporting

confidence: 85%

Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles

Tapper

Karlsson

Mörgelin

et al. 2002

Blood

156

172

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Human neutrophils have an important role in host defense against microbial infection. At different stages of an infectious process, neutrophils progressively up-regulate receptors and release various effector molecules. These are stored in several distinct types of granules with varying propensity to be secreted. Heparin-binding protein (HBP), also known as CAP37 or azurocidin, is a multifunctional, inactive serine-protease homologue. The present work shows that HBP is released from neutrophils on stimulation with secretagogues that do not trigger the secretion of azurophilic granule content. Therefore, the subcellular localization of HBP was investigated in more detail. Immunofluorescence microscopy revealed that HBP was localized close to the plasma membrane. Further analysis by fractionation of postnuclear supernatants from cavitated neutrophils showed that HBP is stored in azurophilic granules and secretory vesicles but that it is also detected to a minor extent in the plasma membrane. IntroductionPolymorphonuclear leukocytes (PMNs) have an important role in early host defense against invading microorganisms (for reviews, see references 1 and 2). Recruitment of these cells from the bloodstream to a site of infection involves their recognition of inflammatory mediators, their binding to adhesion molecules of the vascular endothelium, and their migration across the endothelial barrier. 3 How efficiently neutrophils perform these tasks depends on a sophisticated mobilization mechanism that triggers the release of granule contents and the concomitant up-regulation of various receptors to the plasma membrane. 4 Secretory processes are also important for the extravascular migration of neutrophils through tissues. Once the cells have reached the focus of infection, they are fully activated and are able to fight the infection by secreting reactive oxygen intermediates, antimicrobial peptides, and degradative enzymes. 2 These substances can be preferentially targeted to phagosome compartments to achieve efficient killing and degradation of internalized microorganisms.Lately, much interest has been focused on the various granule types of neutrophils and their sequential mobilization during the inflammatory process (for review, see reference 5). Analysis of these granules by electron microscopy and subcellular fractionation has demonstrated that neutrophils have at least 4 different granule or vesicle types. [6][7][8][9] These are the primary or azurophilic granules that contain myeloperoxidase (MPO), bactericidal proteins, and proteinases; the secondary or specific granules that store lactoferrin and enzymes such as collagenase and gelatinase; the tertiary or gelatinase granules that, like specific granules, contain tissuedegrading enzymes; and the secretory vesicles, an easily mobilizable compartment, that contain alkaline phosphatase and plasma proteins such as human serum albumin. The 4 granule types are mobilized at different stages of the inflammatory process; secretory vesicles are more readily secreted than th...

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Section: Discussionsupporting

confidence: 85%

Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles

Tapper

Karlsson

Mörgelin

et al. 2002

Blood

156

172

View full text Add to dashboard Cite

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“…13,45,46 All 3 proteins were previously shown to have monocyte-activating properties. We have earlier demonstrated that HBP activates monocytes via ␤ 2 -integrins, leading to Ca 2ϩ mobilization, 47 monocyte adhesion, 27 and the release of cytokines (O.S., H.H., L.L., manuscript submitted April 2008).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil secretion products pave the way for inflammatory monocytes

Soehnlein

Zernecke

Eriksson

et al. 2008

Blood

368

341

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The leukocyte response in inflammation is characterized by an initial recruitment of polymorphonuclear leukocytes (PMN) preceding a second wave of monocytes to the site of injury or infection. In the mouse, 2 populations of monocytes have been identified, Gr1 ؊ CCR2 ؊ CX3CR1 hi resident monocytes and Gr1 ؉ CCR2 ؉ CX3CR1 lo inflammatory monocytes. Here, intravital microscopy of the musculus cremaster and a subcutaneous air pouch model were used to investigate a possible link between PMN extravasation and the subsequent emigration of inflammatory monocytes in response to local stimulation with PAF. In mice that were made neutropenic by injection of a PMNdepleting antibody, the extravasation of inflammatory monocytes, but not resident monocytes, was markedly reduced compared with mice with intact white blood cell IntroductionPolymorphonuclear leukocytes (PMN) dominate the initial leukocyte influx to sites of acute infection and inflammation. 1 This first wave of PMN extravasation precedes a second wave of monocyte extravasation. Recruited PMN are thought to trigger this cellular switch by releasing soluble factors that initiate monocyte recruitment, 2-4 much of which may be mediated by ready-made PMN granule proteins deposited at the site of inflammation. 5,6 Indeed, supernatants of activated PMN from patients with specific granule deficiency lacking proteins in their primary, secondary, and tertiary granules show a reduced capacity to attract monocytes despite normal monocyte chemotaxis in vitro to other stimuli. 7 After this initial observation, several PMN-derived granule proteins with monocyte-chemotactic activity were identified, among them LL-37, cathepsin G, human neutrophil peptide 1-3 (HNP1-3, ␣-defensins), and heparin-binding protein (HBP, also known as CAP37 and azurocidin). [8][9][10][11] Their action was found to be pertussis toxin (PTx)-sensitive and several receptors were suggested to mediate the chemotactic effect. [11][12][13] Peripheral blood monocytes constitute a heterogeneous population of circulating leukocytes in both humans 14 and mice. 15 In the murine blood, 2 monocyte subsets can be distinguished based on their expression of CX3CR1, CCR2, and Gr1. Whereas resident monocytes (Gr1 Ϫ CCR2 Ϫ CX3CR1 hi ) home to noninflamed tissues, inflammatory monocytes (Gr1 ϩ CCR2 ϩ CX3CR1 lo ) are predominantly recruited to sites of inflammation by mechanisms involving CCR2. 15 These inflammatory monocytes were recently shown to be of critical importance in diverse inflammatory and infectious diseases. [16][17][18][19] In this study, we investigated the significance of the initial PMN efflux for the subsequent extravasation of monocytes. Our results demonstrate that PMN seed granule proteins in the tissue which contribute to mobilization specifically of inflammatory monocytes. Functionally, the PMN-dependent invasion of inflammatory monocytes results in a more vigorous immune response as shown by enhanced cytokine release and bacterial clearance at the site of inflammation. Methods AnimalsWild-type C57BL/...

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“…HBP is known as a potent chemoattractant for monocytes (15,26,27), but may also stimulate chemotaxis of T cells and neutrophils (28,29). However, the effect on leukocyte arrest was specific for monocytes, suggesting that this molecule represents a pathway by which monocytes can be recruited selectively.…”

Section: Discussionmentioning

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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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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CAP37, a neutrophil-derived multifunctional inflammatory mediator

Cited by 91 publications

References 70 publications

Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles

Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles

Neutrophil secretion products pave the way for inflammatory monocytes

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

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