Aims The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. Methods and results Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E–deficient (Apoe−/−) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. Conclusion Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.

中文翻译：

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Interleukin-1 受体辅助蛋白阻断可限制动脉粥样硬化的发展并减少斑块炎症

目的 IL-1 受体辅助蛋白 (IL1RAP) 是通过 IL-1、IL-33 和 IL-36 受体发出信号所需的辅助受体。使用新型抗 IL1RAP 阻断抗体，我们研究了 IL1RAP 在动脉粥样硬化中的作用。方法和结果人类动脉粥样硬化斑块的单细胞 RNA 测序数据揭示了 IL1RAP 和几种 IL1RAP 相关细胞因子和受体（包括 IL1B 和 IL33）的表达。组织学分析显示斑块和外膜中均存在 IL1RAP，小鼠动脉粥样硬化主动脉的流式细胞术显示斑块白细胞（包括中性粒细胞和巨噬细胞）上有 IL1RAP 表达。高胆固醇饮食喂养的载脂蛋白 E 缺陷 (Apoe−/−) 小鼠在最后 6 周的饮食中使用新型非消耗性 IL1RAP 阻断抗体或同型对照进行治疗。与对照小鼠相比，IL1RAP 阻断小鼠导致瓣膜下斑块大小减少 20%，并限制斑块中中性粒细胞和单核细胞/巨噬细胞以及外膜中 T 细胞的积累。抗 IL1RAP 治疗小鼠的头臂动脉中与白细胞募集相关的几种基因（包括 Cxcl1 和 Cxcl2）的表达减少，表明斑块炎症减轻，并且这些趋化因子在人类斑块中的表达主要限于 CD68+ 骨髓细胞。此外，体外研究表明，IL-1、IL-33 和 IL-36 诱导巨噬细胞和成纤维细胞释放 CXCL1，而 IL1RAP 阻断可以减轻这种释放。结论 限制动脉粥样硬化小鼠中 IL1RAP 依赖性细胞因子信号通路可减少斑块负荷和斑块炎症，这可能是通过限制斑块趋化因子的产生来实现的。