Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting

Christos Kontos, Omar El Bounkari, Christine Krammer, Dzmitry Sinitski, Kathleen Hille, Chunfang Zan, Guangyao Yan, Sijia Wang, Ying Gao, Markus Brandhofer, Remco T. A. Megens, Adrian Hoffmann, Jessica Pauli, Yaw Asare, Simona Gerra, Priscila Bourilhon, Lin Leng, Hans-Henning Eckstein, Wolfgang E. Kempf, Jaroslav PelisekOzgun Gokce, Lars Maegdefessel, Richard Bucala, Martin Dichgans, Christian Weber, Aphrodite Kapurniotu*, Juergen Bernhagen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

Abstract

Targeting a specific chemokine/receptor axis in atherosclerosis remains challenging. Soluble receptor-based strategies are not established for chemokine receptors due to their discontinuous architecture. Macrophage migration-inhibitory factor (MIF) is an atypical chemokine that promotes atherosclerosis through CXC-motif chemokine receptor-4 (CXCR4). However, CXCR4/CXCL12 interactions also mediate atheroprotection. Here, we show that constrained 31-residue-peptides ('msR4Ms') designed to mimic the CXCR4-binding site to MIF, selectively bind MIF with nanomolar affinity and block MIF/CXCR4 without affecting CXCL12/CXCR4. We identify msR4M-L1, which blocks MIF- but not CXCL12-elicited CXCR4 vascular cell activities. Its potency compares well with established MIF inhibitors, whereas msR4M-L1 does not interfere with cardioprotective MIF/CD74 signaling. In vivo-administered msR4M-L1 enriches in atherosclerotic plaques, blocks arterial leukocyte adhesion, and inhibits atherosclerosis and inflammation in hyperlipidemic Apoe(-/-) mice in vivo. Finally, msR4M-L1 binds to MIF in plaques from human carotid-endarterectomy specimens. Together, we establish an engineered GPCR-ectodomain-based mimicry principle that differentiates between disease-exacerbating and -protective pathways and chemokine-selectively interferes with atherosclerosis. The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.

Original languageEnglish
Article number5981
Number of pages18
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 25 Dec 2020

Keywords

  • MIGRATION-INHIBITORY FACTOR
  • CELL-DERIVED FACTOR-1-ALPHA
  • FACTOR MIF
  • CYTOKINE
  • ATHEROSCLEROSIS
  • EXPRESSION
  • BINDING
  • CXCL12
  • MOUSE
  • LIGAND

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