title: 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.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedrich
authors.forename: Astrid
authors.initials: A
authors.lastname: Kehlen
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gans
authors.forename: Martin
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: Jens-Ulrich
authors.initials: JU
authors.lastname: Rahfeld
authors.forename: Raik
authors.initials: R
authors.lastname: Wolf
authors.forename: Michael
authors.initials: M
authors.lastname: Wermann
authors.forename: Anett
authors.initials: A
authors.lastname: Stephan
authors.forename: Monique
authors.initials: M
authors.lastname: Haegele
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sedlmeier
authors.forename: Sigrid
authors.initials: S
authors.lastname: Graubner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jagla
authors.forename: Anke
authors.initials: A
authors.lastname: Müller
authors.forename: Rico
authors.initials: R
authors.lastname: Eichentopf
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.forename: Franziska
authors.initials: F
authors.lastname: Seifert
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.forename: Isabel
authors.initials: I
authors.lastname: Hesse
authors.forename: Daniela
authors.initials: D
authors.lastname: Trautwein
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wollert
authors.forename: Sabine
authors.initials: S
authors.lastname: Berg
authors.forename: Ernst-Joachim
authors.initials: EJ
authors.lastname: Freyse
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D007527:Isoenzymes; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase