Abstract
Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory disease causes increased vascular permeability and edema formation through unknown mechanisms. Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration in endothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining, leukocytic β2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophil cationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gap formation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvessels in vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducing endothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derived HBP in the vascular response to neutrophil trafficking in inflammation. Targeting this molecule in inflammatory disease conditions offers a new strategy for prevention of endothelial barrier dysfunction caused by misdirected leukocyte activation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Michel, C.C. & Curry, F.E. Microvascular permeability. Physiol. Rev. 79, 703–761 (1999)
Wedmore, C.V. & Williams, T.J. Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 289, 646–650 (1981).
Arfors, K.E. et al. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 69, 338–340 (1987).
Kaslovsky, R.A. et al. Pulmonary edema induced by phagocytosing neutrophils. Protective effect of monoclonal antibody against phagocyte CD18 integrin. Circ. Res. 67, 795–802 (1990).
Edens, H.A. & Parkos, C.A. Modulation of epithelial and endothelial paracellular permeability by leukocytes. Adv. Drug Deliver. Rev. 41, 315–328 (2000).
Gautam, N., Herwald, H., Hedqvist, P. & Lindbom, L. Signaling via beta(2) integrins triggers neutrophil-dependent alteration in endothelial barrier function. J. Exp. Med. 191, 1829–1839 (2000).
Flodgaard, H. et al. Covalent structure of two novel neutrophile leucocyte-derived proteins of porcine and human origin: neutrophile elastase homologues with strong monocyte and fibroblast chemotactic activities. Eur. J. Biochem. 197, 535–547 (1991).
Gabay, J.E. et al. Antibiotic proteins of human polymorphonuclear leukocytes. Proc. Natl. Acad. Sci. USA 86, 5610–5614 (1989).
Pereira, H.A., Shafer, W.M., Pohl, J., Martin, L.E. & Spitznagel, J.K. CAP37, a human neutrophil-derived chemotactic factor with monocyte specific activity. J. Clin. Invest. 85, 1468–1476 (1990).
Borregaard, N. & Cowland, J.B. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 89, 3503–3521 (1997).
Petersen, L.C., Birktoft, J.J. & Flodgaard H. Binding of bovine pancreatic trypsin inhibitor to heparin binding protein/CAP37/azurocidin. Interaction between a Kunitz-type inhibitor and a proteolytically inactive serine proteinase. Eur. J. Biochem. 214, 271–279 (1993).
Kastrup, J.S. et al. Two mutants of human heparin binding protein (CAP37): Toward the understanding of the nature of lipid A/LPS and BPTI binding. Proteins 42, 442–451 (2001).
Iversen, L.F. et al. Structure of HBP, a multifunctional protein with a serine proteinase fold. Nature Struct. Biol. 4, 265–268 (1997).
Nicholls, A., Sharp, K.A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281–296 (1991).
Henson, P.M. & Johnston, R.B. Jr. Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J. Clin. Invest. 79, 669–674 (1987).
Dallegri, F. & Ottonello, L. Tissue injury in neutrophilic inflammation. Inflamm. Res. 46, 382–391 (1997).
Pereira, H.A., Erdem, I., Pohl, J. & Spitznagel, J.K. Synthetic bactericidal peptide based on CAP37: a 37-kD human neutrophil granule-associated cationic antimicrobial protein chemotactic for monocytes. Proc. Natl. Acad. Sci. USA 90, 4733–4737 (1993).
Olofsson, A.M. et al. Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis. J. Clin. Invest. 104, 885–894 (1999).
Chertov, O. et al. Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J. Biol. Chem. 271, 2935–2940 (1996).
Pereira, H.A. CAP37, a neutrophil-derived multifunctional inflammatory mediator. J. Leukoc. Biol. 57, 805–812 (1995).
Morgan, J.G. et al. Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes. J. Immunol. 147, 3210–3214 (1991).
Almeida, R.P., Melchior, M., Campanelli, D., Nathan, C. & Gabay, J.E. Complementary DNA sequence of human neutrophil azurocidin, an antibiotic with extensive homology to serine proteases. Biochem. Biophys. Res. Commun. 177, 688–695 (1991).
Aveskogh, M., Lutzelschwab, C., Huang, M.R. & Hellman, L. Characterization of cDNA clones encoding mouse proteinase 3 (myeloblastine) and cathepsin G. Immunogenetics 46, 181–191 (1997).
Gautam, N., Hedqvist, P. & Lindbom, L. Kinetics of leukocyte-induced changes in endothelial barrier function. Br. J. Pharmacol. 125, 1109–1114 (1998).
Rosengren, S. & Arfors, K.E. Polycations induce microvascular leakage of macromolecules in hamster cheek pouch. Inflammation 15, 159–172 (1991).
Peterson, M.W., Stone, P. & Shasby, D.M. Cationic neutrophil proteins increase transendothelial albumin movement. J. Appl. Physiol. 62, 1521–1530 (1987).
Peters, D.C. & Noble, S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 57, 233–260 (1999).
Lindmark, A., Garwicz, D., Rasmussen, P.B., Flodgaard, H. & Gullberg, U. Characterization of the biosynthesis, processing, and sorting of human HBP/CAP37/azurocidin. J. Leukoc. Biol. 66, 634–643 (1999).
Rasmussen, P.B. et al. Characterization of recombinant human HBP/CAP37/azurocidin, a pleiotropic mediator of inflammation-enhancing LPS-induced cytokine release from monocytes. FEBS Lett. 390, 109–112 (1996).
Raud, J. & Lindbom, L. in Immunopharmacology of the microcirculation. The Handbook of Immunopharmacology (ed. Brain, S.) 127–170 (Academic, London, 1994)
Acknowledgements
This study was supported by the Swedish Medical Research Council (14X-4342), the Swedish Foundation for Health Care Sciences and Allergy Research (A2001 068), the Swedish National Board for Laboratory Animals, IngaBritt and Arne Lundbergs Foundation, and Karolinska Institutet.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gautam, N., Maria Olofsson, A., Herwald, H. et al. Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 7, 1123–1127 (2001). https://doi.org/10.1038/nm1001-1123
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1001-1123
This article is cited by
-
Diagnostic value of plasma heparin-binding protein and the heparin-binding protein-to-albumin ratio in patients with community-acquired Pneumonia: a retrospective study
BMC Infectious Diseases (2023)
-
AZU1 (HBP/CAP37) and PRKCG (PKC-gamma) may be candidate genes affecting the severity of acute mountain sickness
BMC Medical Genomics (2023)
-
Neutrophil degranulation and myocardial infarction
Cell Communication and Signaling (2022)
-
The glycocalyx as a permeability barrier: basic science and clinical evidence
Critical Care (2022)
-
Dynamic changes in heparin-binding protein as a prognostic biomarker for 30-day mortality in sepsis patients in the intensive care unit
Scientific Reports (2022)