Aims In the context of atherosclerosis, macrophages exposed to oxidized low-density lipoprotein (oxLDL) exhibit cellular abnormalities, specifically in adhesome functions, yet the mechanisms and implications of these adhesive dysfunctions remain largely unexplored. Methods and Results This study reveals a significant depletion of Kindlin3 (K3) or Fermt3, an essential component of the adhesome regulating integrin functions, in macrophages located within atherosclerotic plaques in vivo and following oxLDL exposure in vitro. To examine the effects of K3 deficiency, the study utilized hyperlipidemic bone marrow chimeras devoid of myeloid Kindlin3 expression. Absence of myeloid K3 increased atherosclerotic plaque burden in the aortas in vivo and enhanced lipid accumulation and lipoprotein uptake in macrophages from Kindlin3-null chimeric mice in vitro. Importantly, re-expression of K3 in macrophages ameliorated these abnormalities. RNA sequencing of bone marrow-derived macrophages (BMDM) from K3-deficient mice revealed extensive deregulation in adhesion-related pathways, echoing changes observed in wild-type cells treated with oxLDL. Notably, there was an increase in Olr1 expression (encoding the Lectin-like oxidized LDL receptor-1 or LOX1), a gene implicated in atherogenesis. The disrupted K3-integrin axis in macrophages led to a significant elevation in the LOX1 receptor, contributing to increased oxLDL uptake and foam cell formation. Inhibition of LOX1 normalized lipid uptake in Kindlin3 null macrophages. A similar proatherogenic phenotype, marked by increased macrophage LOX1 expression and foam cell formation, was observed in myeloid-specific Itgβ1-deficient mice but not in Itgβ2-deficient mice, underscoring the critical role of K3/Itgβ1 interaction. Conclusion This study shows that the loss of Kindlin3 in macrophages upon exposure to oxLDL leads to adhesome dysfunction in atherosclerosis and reveals the pivotal role of Kindlin3 in macrophage function and its contribution to the progression of atherosclerosis, providing valuable insights into the molecular mechanisms that could be targeted for therapeutic interventions.

中文翻译：

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髓系粘附体功能障碍在动脉粥样硬化形成中的机制和后果


目的 在动脉粥样硬化的情况下，暴露于氧化低密度脂蛋白 （oxLDL） 的巨噬细胞表现出细胞异常，特别是在粘附功能方面，但这些粘附功能障碍的机制和影响在很大程度上仍未得到探索。方法和结果 本研究揭示了 Kindlin3 （K3） 或 Fermt3 的显着消耗，这是粘附体调节整合素功能的重要组成部分，在体内和体外暴露于 oxLDL 后。为了检查 K3 缺陷的影响，该研究使用了没有髓系 Kindlin3 表达的高脂血症骨髓嵌合体。髓系 K3 的缺乏在体内增加了主动脉中的动脉粥样硬化斑块负荷，并在体外增强了 Kindlin3 缺失嵌合小鼠巨噬细胞中的脂质积累和脂蛋白摄取。重要的是，巨噬细胞中 K3 的重新表达改善了这些异常。来自 K3 缺陷小鼠的骨髓来源的巨噬细胞 （BMDM） 的 RNA 测序揭示了粘附相关通路的广泛失调，这与在用 oxLDL 处理的野生型细胞中观察到的变化相呼应。值得注意的是，Olr1 表达（编码凝集素样氧化 LDL 受体-1 或 LOX1）增加，该基因与动脉粥样硬化形成有关。巨噬细胞中 K3-整合素轴的破坏导致 LOX1 受体显着升高，导致 oxLDL 摄取增加和泡沫细胞形成。抑制 LOX1 使 Kindlin3 缺失巨噬细胞的脂质摄取正常化。在骨髓特异性 Itgβ1 缺陷小鼠中观察到类似的促动脉粥样硬化表型，其特征是巨噬细胞 LOX1 表达增加和泡沫细胞形成，但在 Itgβ2 缺陷小鼠中未观察到，强调了 K3/Itgβ1 相互作用的关键作用。 结论 本研究显示，暴露于 oxLDL 后巨噬细胞中 Kindlin3 的缺失导致动脉粥样硬化粘附功能障碍，并揭示了 Kindlin3 在巨噬细胞功能中的关键作用及其对动脉粥样硬化进展的贡献，为可能针对治疗干预的分子机制提供了有价值的见解。