Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
Year: 2020
Type: article
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.
Source: Nature Communications
Authors: 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 Pelisek, Ozgun Gokce, Lars Maegdefessel, Richard Bucala, Martin Dichgans, Christian Weber, Aphrodite Kapurniotu, Jürgen Bernhagen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,628
Funders: U.S. Department of Health and Human Services, Deutsche Forschungsgemeinschaft, Technische Universität München, Ludwig-Maximilians-Universität München, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1488474969, G1563605134, G1789099517, G1901460537, G2214993168, Mechanisms of Rheumatoid Synovial Fibroblast Activation, G2588154941, G3601099971, G3756220908, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G415348097, G4950145638, G4981664119, G5520316217, Yale Clinical and Translational Science Award
OpenAlex ID: W3109224943