Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
VIB Center for Inflammation Research, Technologiepark 927, B-9052, Ghent, Belgium; Department of Biomedical Molecular Biology (DBMB), Ghent University, B-9052, Ghent, Belgium; Methusalem Program CEDAR-IC, Ghent University, B-9052, Ghent, Belgium.
Atherosclerosis. 2021 Apr;322:51-60. doi: 10.1016/j.atherosclerosis.2021.02.021. Epub 2021 Feb 24.
Targeting macrophage death is a promising strategy for stabilizing atherosclerotic plaques. Recently, necroptosis was identified as a form of regulated necrosis in atherosclerosis. Receptor-interacting serine/threonine-protein kinase (RIPK)1 is an upstream regulator of RIPK3, which is a crucial kinase for necroptosis induction. We aimed to investigate the impact of myeloid-specific RIPK1 gene deletion on atherogenesis.
RIPK1LysM-CreApoE and RIPK1LysM-CreApoE mice were fed a western-type diet (WD) for 16 or 24 weeks to induce plaque formation.
After 16 weeks WD, plaque area and percentage necrosis in RIPK1LysM-CreApoE mice were significantly decreased as compared to plaques of RIPK1LysM-CreApoE mice. Moreover, plaques of RIPK1LysM-CreApoE mice showed more apoptosis and a decreased macrophage content. After 24 weeks WD, plaque size and percentage necrosis were no longer different between the two groups. Free apoptotic cells strongly accumulated in plaques of RIPK1LysM-CreApoE mice. In addition to apoptosis, necroptosis was upregulated in plaques of RIPK1LysM-CreApoE mice. In vitro, TNF-α triggered apoptosis in RIPK1LysM-CreApoE, but not in RIPK1LysM-CreApoE macrophages. Moreover, RIPK1LysM-CreApoE macrophages were not protected against RIPK3-dependent necroptosis.
The impact of myeloid RIPK1 gene deletion depends on the stage of atherogenesis. At 16 weeks WD, myeloid RIPK1 gene deletion resulted in increased apoptosis, thereby slowing down plaque progression. However, despite decreased macrophage content, plaque and necrotic core size were no longer reduced after 24 weeks of WD, most likely due to the accumulation of free apoptotic and necroptotic cells.
靶向巨噬细胞死亡是稳定动脉粥样硬化斑块的一种有前途的策略。最近，坏死性凋亡被确定为动脉粥样硬化中的一种受调控的细胞坏死形式。受体相互作用丝氨酸/苏氨酸蛋白激酶（RIPK）1 是 RIPK3 的上游调节因子，RIPK3 是诱导坏死性凋亡的关键激酶。我们旨在研究髓样细胞特异性 RIPK1 基因缺失对动脉粥样硬化形成的影响。
用西方饮食（WD）喂养 RIPK1LysM-CreApoE 和 RIPK1LysM-CreApoE 小鼠 16 或 24 周，以诱导斑块形成。
在 WD 16 周后，与 RIPK1LysM-CreApoE 小鼠的斑块相比，RIPK1LysM-CreApoE 小鼠的斑块面积和坏死百分比明显减少。此外，RIPK1LysM-CreApoE 小鼠的斑块显示出更多的细胞凋亡和巨噬细胞含量减少。在 WD 24 周后，两组之间的斑块大小和坏死百分比不再有差异。游离的凋亡细胞在 RIPK1LysM-CreApoE 小鼠的斑块中大量积累。除了细胞凋亡，RIPK1LysM-CreApoE 小鼠的斑块中还上调了坏死性凋亡。在体外，TNF-α 触发了 RIPK1LysM-CreApoE 而不是 RIPK1LysM-CreApoE 巨噬细胞的细胞凋亡。此外，RIPK1LysM-CreApoE 巨噬细胞不能免受 RIPK3 依赖性坏死性凋亡的保护。
髓样细胞 RIPK1 基因缺失的影响取决于动脉粥样硬化形成的阶段。在 WD 16 周时，髓样细胞 RIPK1 基因缺失导致细胞凋亡增加，从而减缓斑块进展。然而，尽管巨噬细胞含量减少，但在 WD 24 周后，斑块和坏死核心大小不再减少，这很可能是由于游离的凋亡和坏死性凋亡细胞的积累所致。
