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.

针对动脉粥样硬化中的特定趋化因子/受体轴仍然具有挑战性。由于趋化因子受体的不连续结构，尚未建立基于可溶性受体的策略。巨噬细胞迁移抑制因子 (MIF) 是一种非典型趋化因子，通过 CXC 基序趋化因子受体 4 (CXCR4) 促进动脉粥样硬化。然而，CXCR4/CXCL12 相互作用也介导动脉粥样硬化保护。在这里，我们展示了设计用于模拟 CXCR4 与 MIF 结合位点的受限 31 残基肽（“msR4Ms”），以纳摩尔亲和力选择性结合 MIF，并阻断 MIF/CXCR4，而不影响 CXCL12/CXCR4。我们鉴定出 msR4M-L1，它可以阻断 MIF 而不是 CXCL12 引发的 CXCR4 血管细胞活性。其效力与现有的 MIF 抑制剂相当，而 msR4M-L1 不会干扰心脏保护性 MIF/CD74 信号传导。体内施用的 msR4M-L1 可以富集动脉粥样硬化斑块，阻断动脉白细胞粘附，并抑制体内高脂血症Apoe ^-/−小鼠的动脉粥样硬化和炎症。最后，msR4M-L1 与人颈动脉内膜切除术标本斑块中的 MIF 结合。我们共同建立了一种基于 GPCR 胞外域的拟态原理，可区分疾病恶化和保护途径，并通过趋化因子选择性地干扰动脉粥样硬化。