Seminars in Immunopathology

, Volume 35, Issue 4, pp 411–421 | Cite as

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

  • Brice Korkmaz
  • Adam Lesner
  • Stephanie Letast
  • Yassir K. Mahdi
  • Marie-Lise Jourdan
  • Sandrine Dallet-Choisy
  • Sylvain Marchand-Adam
  • Christine Kellenberger
  • Marie-Claude Viaud-Massuard
  • Dieter E. Jenne
  • Francis Gauthier
Review

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.

Keywords

Proteinase 3 Dipeptidyl peptidase I (cathepsin C) Neutrophil Granulomatosis with polyangiitis ANCA 

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

Notes

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Brice Korkmaz
    • 1
    • 2
  • Adam Lesner
    • 3
  • Stephanie Letast
    • 4
  • Yassir K. Mahdi
    • 1
  • Marie-Lise Jourdan
    • 5
    • 6
  • Sandrine Dallet-Choisy
    • 1
  • Sylvain Marchand-Adam
    • 1
  • Christine Kellenberger
    • 7
  • Marie-Claude Viaud-Massuard
    • 4
  • Dieter E. Jenne
    • 8
  • Francis Gauthier
    • 1
  1. 1.“Centre d’Etude des Pathologies Respiratoires”INSERM U-1100/EA-6305ToursFrance
  2. 2.Faculté de MédecineUniversité François RabelaisToursFrance
  3. 3.Faculty of ChemistryUniversity of GdanskGdanskPoland
  4. 4.Génétique, Immunothérapie, Chimie et CancerCNRS UMR-7292/EA-6306ToursFrance
  5. 5.Centre Hospitalier Régional UniversitaireToursFrance
  6. 6.INSERM U-1069ToursFrance
  7. 7.Architecture et Fonction des Macromolécules BiologiquesCNRS UMR7257 and Aix-Marseille UniversitéMarseilleFrance
  8. 8.Comprehensive Pulmonary CenterHelmholtz Center MunichNeuherbergGermany

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