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Neutrophil proteinase 3 and dipeptidyl peptidase I (cathepsin C) as pharmacological targets in granulomatosis with polyangiitis (Wegener granulomatosis)

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Abstract

Neutrophils are among the first cells implicated in acute inflammation. Leaving the blood circulation, they quickly migrate through the interstitial space of tissues and liberate oxidants and other antimicrobial proteins together with serine proteinases. Neutrophil elastase, cathepsin G, proteinase 3 (PR3), and neutrophil serine protease 4 are four hematopoietic serine proteases activated by dipeptidyl peptidase I during neutrophil maturation and are mainly stored in cytoplasmic azurophilic granules. They regulate inflammatory and immune responses after their release from activated neutrophils at inflammatory sites. Membrane-bound PR3 (mbPR3) at the neutrophil surface is the prime antigenic target of antineutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis (GPA), a vasculitis of small blood vessels and granulomatous inflammation of the upper and/or lower respiratory tracts. The interaction of ANCA with mbPR3 results in excessive activation of neutrophils to produce reactive oxygen species and liberation of granular proteinases to the pericellular environment. In this review, we focus on PR3 and dipeptidyl peptidase I as attractive pharmacological targets whose inhibition is expected to attenuate autoimmune activation of neutrophils in GPA.

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Abbreviations

mb:

Membrane-bound

PR3:

Proteinase 3

HNE:

Human neutrophil elastase

CG:

Cathepsin G

MPO:

Myeloperoxidase

NSPs:

Neutral serine proteinases

αl-PI:

α1-Proteinase inhibitor

ANCA:

Antineutrophil cytoplasmic autoantibodies

NET:

Neutrophil extracellular traps

TNF:

Tumor necrosis factor

FRET:

Fluorescence resonance energy transfer

GPA:

Granulomatosis with polyangiitis

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Acknowledgments

This work was supported by “Region Centre,” the “Fonds Européen de Développement Régional” (Projet INFINHI), and “Association Vaincre la Mucoviscidose (VLM)” and has also received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 261382. BK acknowledges the Alexander von Humboldt Foundation. The authors thank Mrs Virginie Malak from Santa Cruz Biotechnology, Inc. for providing the antiDPPI antibody (D-6).

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Authors and Affiliations

  1. “Centre d’Etude des Pathologies Respiratoires”, INSERM U-1100/EA-6305, 37032, Tours, France

    Brice Korkmaz, Yassir K. Mahdi, Sandrine Dallet-Choisy, Sylvain Marchand-Adam & Francis Gauthier

  2. Faculté de Médecine, Université François Rabelais, 37032, Tours, France

    Brice Korkmaz

  3. Faculty of Chemistry, University of Gdansk, Sobieskiego 18, 80-952, Gdansk, Poland

    Adam Lesner

  4. Génétique, Immunothérapie, Chimie et Cancer, CNRS UMR-7292/EA-6306, 37200, Tours, France

    Stephanie Letast & Marie-Claude Viaud-Massuard

  5. Centre Hospitalier Régional Universitaire, 37044, Tours, France

    Marie-Lise Jourdan

  6. INSERM U-1069, 37032, Tours, France

    Marie-Lise Jourdan

  7. Architecture et Fonction des Macromolécules Biologiques, CNRS UMR7257 and Aix-Marseille Université, Marseille, France

    Christine Kellenberger

  8. Comprehensive Pulmonary Center, Helmholtz Center Munich, 85764, Neuherberg, Germany

    Dieter E. Jenne

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  1. Brice Korkmaz
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Correspondence to Brice Korkmaz.

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This article is a contribution to the special issue on Neutrophils - Guest Editors: Paul Hasler and Sinuhe Hahn.

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Korkmaz, B., Lesner, A., Letast, S. et al. Neutrophil proteinase 3 and dipeptidyl peptidase I (cathepsin C) as pharmacological targets in granulomatosis with polyangiitis (Wegener granulomatosis). Semin Immunopathol 35, 411–421 (2013). https://doi.org/10.1007/s00281-013-0362-z

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