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Abstract：
OBJECTIVE: 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.
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.
CONCLUSIONS: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.
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.
CONCLUSIONS: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.
摘要：
目的：白介素-1受体辅助蛋白（IL1RAP）是通过IL-1，IL-33和IL-36受体进行信号传导所需的共受体。使用一种新型的抗IL1RAP阻断抗体，我们研究了IL1RAP在动脉粥样硬化中的作用.
结果：来自人动脉粥样硬化斑块的单细胞RNA测序数据显示IL1RAP和几种IL1RAP相关细胞因子和受体的表达，包括IL1B和IL33。组织学分析显示在斑块和外膜中都存在IL1RAP，小鼠动脉粥样硬化主动脉的流式细胞术显示IL1RAP在斑块白细胞上表达，包括中性粒细胞和巨噬细胞.在最后6周的饮食中，用新型非消耗性IL1RAP阻断抗体或同种型对照对高胆固醇饮食喂养的载脂蛋白E缺陷型（Apo-/-）小鼠进行治疗。小鼠的IL1RAP阻断导致瓣膜下斑块大小减少20％，并限制了斑块中嗜中性粒细胞和单核细胞/巨噬细胞的积累以及外膜中T细胞的积累。与对照小鼠相比。指示减少斑块炎症，与白细胞募集相关的几个基因的表达，包括Cxcl1和Cxcl2，在抗IL1RAP处理的小鼠头臂动脉中减少，这些趋化因子在人斑块中的表达主要局限于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，这可以通过IL1RAP封锁来缓解。
结论：在动脉粥样硬化小鼠中限制IL1RAP依赖性细胞因子信号通路可减少斑块负荷和斑块炎症，可能通过限制斑块趋化因子的产生。
结果：来自人动脉粥样硬化斑块的单细胞RNA测序数据显示IL1RAP和几种IL1RAP相关细胞因子和受体的表达，包括IL1B和IL33。组织学分析显示在斑块和外膜中都存在IL1RAP，小鼠动脉粥样硬化主动脉的流式细胞术显示IL1RAP在斑块白细胞上表达，包括中性粒细胞和巨噬细胞.在最后6周的饮食中，用新型非消耗性IL1RAP阻断抗体或同种型对照对高胆固醇饮食喂养的载脂蛋白E缺陷型（Apo-/-）小鼠进行治疗。小鼠的IL1RAP阻断导致瓣膜下斑块大小减少20％，并限制了斑块中嗜中性粒细胞和单核细胞/巨噬细胞的积累以及外膜中T细胞的积累。与对照小鼠相比。指示减少斑块炎症，与白细胞募集相关的几个基因的表达，包括Cxcl1和Cxcl2，在抗IL1RAP处理的小鼠头臂动脉中减少，这些趋化因子在人斑块中的表达主要局限于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，这可以通过IL1RAP封锁来缓解。
结论：在动脉粥样硬化小鼠中限制IL1RAP依赖性细胞因子信号通路可减少斑块负荷和斑块炎症，可能通过限制斑块趋化因子的产生。
