Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
Institute of Endocrinology, Beilinson Campus, Rabin Medical Center, Petach Tikva, Israel.
Commun Biol. 2022 Feb 15;5(1):132. doi: 10.1038/s42003-022-03078-5.
Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2 activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2 mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.
动脉粥样硬化是一种慢性炎症性疾病，其中巨噬细胞起着主要作用。Janus 激酶 2（JAK2）是炎症和代谢信号转导的关键分子，最近发现 Jak2 激活突变可增强克隆性造血和动脉粥样硬化。为了确定巨噬细胞（M）-Jak2 在动脉粥样硬化中的重要体内作用，我们生成了缺乏 M-Jak2 的易患动脉粥样硬化的 ApoE 基因敲除小鼠。与我们的预期相反，这些小鼠表现出斑块负担增加，而巨噬细胞增殖、募集或骨髓克隆扩增没有差异。值得注意的是，M-Jak2 缺陷型骨髓来源的巨噬细胞显示胆固醇外排明显缺陷。用鲁索替尼进行药理学 JAK2 抑制也会导致胆固醇外排缺陷，并加速动脉粥样硬化的发生。肝 X 受体激动剂可消除外排缺陷，并减轻 M-Jak2 缺乏引起的加速动脉粥样硬化。具有 Jak2 突变的个体的巨噬细胞显示出增加的外排，当用 JAK2 抑制剂治疗时，这种外排会恢复正常。总之，M-Jak2 缺乏主要通过巨噬细胞胆固醇外排缺陷导致加速动脉粥样硬化。
