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

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 pE(1) -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.

• Authors: Holger Cynis, Torsten Hoffmann, Daniel Friedrich, Astrid Kehlen, Kathrin Gans, Martin Kleinschmidt, Jens-Ulrich Rahfeld, Raik Wolf, Michael Wermann, Anett Stephan, Monique Haegele, Reinhard Sedlmeier, Sigrid Graubner, Wolfgang Jagla, Anke Müller, Rico Eichentopf, Ulrich Heiser, Franziska Seifert, Paul H A Quax, Margreet R de Vries, Isabel Hesse, Daniela Trautwein, Ulrich Wollert, Sabine Berg, Ernst-Joachim Freyse, Stephan Schilling, Hans-Ulrich Demuth
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 3 Issue 9 Pg. 545-58 (Sep 2011) ISSN: 1757-4684 [Electronic] England
• PMID: 21774078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 EMBO Molecular Medicine.

Chemical References

• CCL2 protein, human
• Chemokine CCL2
• Isoenzymes
• Aminoacyltransferases
• glutaminyl-peptide cyclotransferase

Topics

• Aminoacyltransferases (metabolism)
• Animals
• Atherosclerosis (immunology, pathology)
• Cell Line
• Cell Movement
• Chemokine CCL2 (antagonists & inhibitors, metabolism)
• Female
• Gene Silencing
• Humans
• Inflammation (immunology, pathology)
• Isoenzymes (metabolism)
• Mice
• Mice, Inbred C57BL
• Monocytes (enzymology, metabolism)