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Designed CXCR4 mimi...
Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
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Kontos, C (author)
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El Bounkari, O (author)
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Krammer, C (author)
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Sinitski, D (author)
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Hille, K (author)
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Zan, CF (author)
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Yan, GY (author)
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Wang, SJ (author)
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Gao, Y (author)
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Brandhofer, M (author)
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Megens, RTA (author)
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Hoffmann, A (author)
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Pauli, J (author)
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Asare, Y (author)
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Gerra, S (author)
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Bourilhon, P (author)
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Leng, L (author)
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Eckstein, HH (author)
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Kempf, WE (author)
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Pelisek, J (author)
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Gokce, O (author)
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- Maegdefessel, L (author)
- Karolinska Institutet
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Bucala, R (author)
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Dichgans, M (author)
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Weber, C (author)
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Kapurniotu, A (author)
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Bernhagen, J (author)
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(creator_code:org_t)
- 2020-11-25
- 2020
- English.
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5981-
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Abstract
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- 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.
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Kontos, C
-
El Bounkari, O
-
Krammer, C
-
Sinitski, D
-
Hille, K
-
Zan, CF
-
show more...
-
Yan, GY
-
Wang, SJ
-
Gao, Y
-
Brandhofer, M
-
Megens, RTA
-
Hoffmann, A
-
Pauli, J
-
Asare, Y
-
Gerra, S
-
Bourilhon, P
-
Leng, L
-
Eckstein, HH
-
Kempf, WE
-
Pelisek, J
-
Gokce, O
-
Maegdefessel, L
-
Bucala, R
-
Dichgans, M
-
Weber, C
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Kapurniotu, A
-
Bernhagen, J
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show less...
- Articles in the publication
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Nature communica ...
- By the university
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Karolinska Institutet