Open AccessThe isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions
Author(s) -
Cynis Holger,
Hoffmann Torsten,
Friedrich Daniel,
Kehlen Astrid,
Gans Kathrin,
Kleinschmidt Martin,
Rahfeld JensUlrich,
Wolf Raik,
Wermann Michael,
Stephan Anett,
Haegele Monique,
Sedlmeier Reinhard,
Graubner Sigrid,
Jagla Wolfgang,
Müller Anke,
Eichentopf Rico,
Heiser Ulrich,
Seifert Franziska,
Quax Paul H. A.,
de Vries Margreet R.,
Hesse Isabel,
Trautwein Daniela,
Wollert Ulrich,
Berg Sabine,
Freyse ErnstJoachim,
Schilling Stephan,
Demuth HansUlrich
Publication year - 2011
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201100158
Subject(s) - regulator , infiltration (hvac) , monocyte , chemistry , inflammation , microbiology and biotechnology , isozyme , biochemistry , enzyme , biology , immunology , materials science , composite material , gene
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.