Pilot Thomas, Solier Stéphanie, Jalil Antoine, Magnani Charlène, Vanden Berghe Tom, Vandenabeele Peter, Masson David, Solary Eric, Thomas Charles
Université de Bourgogne, Center for Translational and Molecular Medicine (CTM) Unité Mixte de Recherche (UMR) 1231, Dijon, France.
Institut national de la santé et de la recherche médicale (INSERM), UMR1231, Dijon, France.
Front Immunol. 2025 Apr 8;16:1513637. doi: 10.3389/fimmu.2025.1513637. eCollection 2025.
Cell death plays a central role in atheroma plaque progression and aggravation. This study investigates the role of caspase-8 in regulating macrophage cell death modalities, specifically apoptosis and necroptosis, within atheroma plaques.
Bone marrow from caspase-8-deficient ( ) and cohoused wildtype littermates were transplanted in atherosclerosis-prone recipient mice fed with a proatherogenic diet. Aortic plaque development, necrotic core formation, and cell death were analyzed through histological and biochemical assays. investigation of macrophages exposed to atherogenic stimuli assessed the effects of caspase-8 inhibition on apoptotic and necroptotic pathways.
Despite lower plasma cholesterol levels and reduced number of inflammatory monocytes, caspase-8-deficient mice exhibited more pronounced atherosclerotic lesions with enlarged necrotic cores and an increased number of dead cells. , in macrophages exposed to oxidized LDL or oxysterols, the inhibition of caspase-8 revealed a shift from apoptosis to necroptosis as confirmed by increased phosphorylation of MLKL along with decreased cleavage of caspase-3 and -7.
The study highlights the role of caspase-8 in atherosclerosis in tuning the balance between apoptosis and necroptosis. Caspase-8 inhibition leads to a switch towards necroptosis and accumulation of dead cell corpses that contributes to enhanced plaque severity. These findings suggest that reducing caspase-8-regulated necroptosis and necrosis in macrophages could represent a therapeutic strategy to stabilize plaques and reduce cardiovascular risk.
细胞死亡在动脉粥样硬化斑块进展和加重过程中起核心作用。本研究调查了半胱天冬酶 - 8在调节动脉粥样硬化斑块内巨噬细胞死亡方式（特别是凋亡和坏死性凋亡）中的作用。
将来自半胱天冬酶 - 8缺陷型（ ）和同笼饲养的野生型同窝小鼠的骨髓移植到易患动脉粥样硬化的 受体小鼠中，这些小鼠喂食致动脉粥样硬化饮食。通过组织学和生化分析评估主动脉斑块发展、坏死核心形成和细胞死亡情况。对暴露于致动脉粥样硬化刺激的巨噬细胞进行研究，评估半胱天冬酶 - 8抑制对凋亡和坏死性凋亡途径的影响。
尽管半胱天冬酶 - 8缺陷型小鼠血浆胆固醇水平较低且炎症单核细胞数量减少，但它们表现出更明显的动脉粥样硬化病变，坏死核心增大且死亡细胞数量增加。此外，在暴露于氧化低密度脂蛋白或氧化甾醇的巨噬细胞中，半胱天冬酶 - 8的抑制显示出从凋亡向坏死性凋亡的转变，这通过混合谱系激酶结构域样蛋白（MLKL）磷酸化增加以及半胱天冬酶 - 3和 - 7裂解减少得以证实。
该研究强调了半胱天冬酶 - 8在动脉粥样硬化中调节凋亡和坏死性凋亡平衡的作用。半胱天冬酶 - 8抑制导致向坏死性凋亡的转变以及死亡细胞尸体的积累，这有助于增强斑块严重程度。这些发现表明，减少巨噬细胞中半胱天冬酶 - 8调节的坏死性凋亡和坏死可能代表一种稳定斑块和降低心血管风险的治疗策略。
