Li Tianhan, Lu Liaoxun, Qiu Juanjuan, Dong Xin, Yang Le, He Kexin, Gu Yanrong, Zhou Binhui, Jia Tingting, Lawrence Toby, Malissen Marie, Wang Guixue, Huang Rong, Wang Hui, Malissen Bernard, Liang Yinming, Zhang Lichen
School of Basic Medicine, Xinxiang Medical University, Xinxiang, China.
School of Medical Technology, Xinxiang Medical University, Xinxiang, China.
Elife. 2025 Sep 11;14:RP107742. doi: 10.7554/eLife.107742.
Atherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however, the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1 cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in atherosclerosis development remains highly controversial. We first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4 and CD8 subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1 cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1 cDC1 cells via Xcl1 by establishing mice. mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. Our results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.
动脉粥样硬化的特征是斑块内脂质堆积，导致泡沫细胞形成以及主动脉病变内的炎症反应。脂质紊乱已得到广泛研究，然而，引发动脉粥样硬化斑块炎症反应的细胞和分子机制仍远未完全阐明。Xcr1⁺ cDC1细胞是新发现的在激活免疫细胞方面起作用的抗原呈递细胞。然而，cDC1细胞在动脉粥样硬化发展中的作用仍极具争议。我们首先证实了人类动脉粥样硬化斑块中存在cDC1，并发现小鼠体内cDC1数量增加与动脉粥样硬化进展之间存在显著关联。随后，我们建立了一种新型复杂基因模型小鼠，在动脉粥样硬化发展过程中cDC1在体内持续缺失。有趣的是，我们观察到高脂血症小鼠的动脉粥样硬化病变显著减少，同时主动脉斑块中CD4和CD8亚群的T细胞激活受到抑制。值得注意的是，cDC1缺失小鼠的主动脉巨噬细胞和血清脂质水平没有显著变化。单细胞RNA测序揭示了高脂血症条件下主动脉和淋巴器官中Xcr1⁺ cDC1细胞的异质性。由于Xcr1是Xcl1的唯一受体，我们接下来通过建立Xcl1⁻/⁻小鼠探索通过Xcl1靶向Xcr1⁺ cDC1细胞。Xcl1⁻/⁻小鼠表现出动脉粥样硬化斑块形成减少和主动脉cDC1积聚减少，表明Xcl1促进cDC1介导的动脉粥样硬化病变发展。我们的结果揭示了cDC1在动脉粥样硬化进展中的关键作用，并为通过Xcl1靶向cDC1开发免疫疗法提供了见解。
