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.
Highlights
Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression
CCL2 is a key mediator for the infiltration of monocytes to inflamed tissues and plays a pivotal role in several inflammatory disorders, such as atherosclerosis (Boring et al, 1998; Gosling et al, 1999; Mori et al, 2002), cancer (Fridlender et al, 2010), pancreatitis (Marra, 2005), Alzheimer’s disease (Galimberti et al, 2006) or multiple sclerosis (Gerard & Rollins, 2001)
The results presented here introduce a novel mechanism to reduce the activity of CCL2 under different inflammatory conditions (Fig 7)
Summary
Acute and chronic inflammatory disorders are characterized by detrimental cytokine and chemokine expression. The N-terminus of monocyte chemoattractant protein 1 (CCL2 and MCP-1) is modified to a pyroglutamate (pE-) residue protecting against degradation in vivo. 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. 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. The pE-residue confers resistance against degradation by aminopeptidases and—as has been already shown for TRH and GnRH—is important for the receptor interaction (Abraham & Podell, 1981; Morty et al, 2006). Inhibition of QC-activity has been shown to prevent pE-peptide formation in mammalian cells (Buchholz et al, 2006; Cynis et al, 2006)
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