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The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions

  1. Holger Cynis1,
  2. Torsten Hoffmann1,
  3. Daniel Friedrich1,
  4. Astrid Kehlen1,
  5. Kathrin Gans1,
  6. Martin Kleinschmidt1,
  7. Jens-Ulrich Rahfeld1,
  8. Raik Wolf1,
  9. Michael Wermann1,
  10. Anett Stephan1,
  11. Monique Haegele1,
  12. Reinhard Sedlmeier2,
  13. Sigrid Graubner2,
  14. Wolfgang Jagla2,
  15. Anke Müller2,
  16. Rico Eichentopf1,
  17. Ulrich Heiser1,
  18. Franziska Seifert3,
  19. Paul H. A. Quax4,
  20. Margreet R. de Vries4,
  21. Isabel Hesse5,
  22. Daniela Trautwein5,
  23. Ulrich Wollert5,
  24. Sabine Berg6,
  25. Ernst-Joachim Freyse6,
  26. Stephan Schilling1,*,
  27. Hans-Ulrich Demuth1,2

Article first published online: 20 JUL 2011

DOI: 10.1002/emmm.201100158

Issue

EMBO Molecular Medicine

EMBO Molecular Medicine

Volume 3, Issue 9, pages 545–558, September 2011

Additional Information

How to Cite

Cynis, H., Hoffmann, T., Friedrich, D., Kehlen, A., Gans, K., Kleinschmidt, M., Rahfeld, J.-U., Wolf, R., Wermann, M., Stephan, A., Haegele, M., Sedlmeier, R., Graubner, S., Jagla, W., Müller, A., Eichentopf, R., Heiser, U., Seifert, F., Quax, P. H. A., de Vries, M. R., Hesse, I., Trautwein, D., Wollert, U., Berg, S., Freyse, E.-J., Schilling, S. and Demuth, H.-U. (2011), The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO Mol Med, 3: 545–558. doi: 10.1002/emmm.201100158

Author Information

  1. 1

    Probiodrug AG, Halle, Germany

  2. 2

    Ingenium Pharmaceuticals GmbH, Martinsried, Germany

  3. 3

    Albrecht-von-Haller-Institute, Georg-August University, Göttingen, Germany

  4. 4

    Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands

  5. 5

    Department for Vascular Surgery, St. Elisabeth and St. Barbara Hospital, Halle, Germany

  6. 6

    Institute of Diabetes, Karlsburg, Germany

*Tel: +49 345 555 99 11, Fax: +49 345 555 99 01

Publication History

  1. Issue published online: 1 SEP 2011
  2. Article first published online: 20 JUL 2011
  3. Manuscript Accepted: 8 JUN 2011
  4. Manuscript Revised: 1 JUN 2011
  5. Manuscript Received: 18 MAR 2011

Funded by

  • Investment Bank of Saxony-Anhalt. Grant Number: #6003373000

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Keywords:

  • CCL2;
  • drug development;
  • glutaminyl cyclases;
  • inflammation;
  • pyroglutamate

Abstract

Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. Frequently, the chemotactic activity of cytokines depends on a modified N-terminus of the polypeptide. Among those, the N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. Here, we show that the N-terminal pE-formation depends on glutaminyl cyclase activity. The pE-residue increases stability against N-terminal degradation by aminopeptidases and improves receptor activation and signal transduction in vitro. Genetic ablation of the glutaminyl cyclase iso-enzymes QC (QPCT) or isoQC (QPCTL) revealed a major role of isoQC for pE1-CCL2 formation and monocyte infiltration. Consistently, administration of QC-inhibitors in inflammatory models, such as thioglycollate-induced peritonitis reduced monocyte infiltration. The pharmacologic efficacy of QC/isoQC-inhibition was assessed in accelerated atherosclerosis in ApoE3*Leiden mice, showing attenuated atherosclerotic pathology following chronic oral treatment. Current strategies targeting CCL2 are mainly based on antibodies or spiegelmers. The application of small, orally available inhibitors of glutaminyl cyclases represents an alternative therapeutic strategy to treat CCL2-driven disorders such as atherosclerosis/restenosis and fibrosis.

→See accompanying article http://dx.doi.org/10.1002/emmm.201100161

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