Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels.
Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels.
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DOI：
10.1161/atvbaha.117.310607
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
Deckelbaum RJ
中科院分区：
文献类型：
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作者：
Chang CL;Garcia-Arcos I;Nyrén R;Olivecrona G;Kim JY;Hu Y;Agrawal RR;Murphy AJ;Goldberg IJ;Deckelbaum RJ
组织巨噬细胞诱导并维持促炎反应，从而促进代谢和心血管疾病。脂蛋白脂酶（LpL）是血液甘油三酯（TG）催化剂的限速酶，由动脉粥样硬化斑块中的巨噬细胞表达。我们质疑LpL是否也在骨髓（BM）中表达，是否影响循环白色血细胞（WBC）和BM增殖，并调节动脉内的巨噬细胞滞留。我们的特点是血液和组织中的白细胞和炎症分子在转基因LpL基因敲除小鼠从致命的高脂血症在18小时内的生命由肌肉特异性LpL表达（MCKL 0小鼠）。LpL缺陷小鼠的血液WBC、中性粒细胞以及总单核细胞和炎性单核细胞（Ly 6C/Ghi）减少约40%。LpL缺乏还显著降低了BM巨噬细胞相关标志物（F4/80和TNF-α）、主转录因子（PU.1和C/EBPα）和集落刺激因子（CSF）及其受体（CSF-Rs）的表达，这些因子是单核细胞和单核细胞前体细胞增殖和分化所必需的。结果，在MCKL 0小鼠中，来自BM来源的单核细胞祖细胞和单核细胞的巨噬细胞的分化减少。此外，虽然LpL缺乏与BM摄取减少和富含TG颗粒的积累以及M-CSF-M-CSF-R结合有关，但TG脂解产物（例如，亚油酸）刺激BM衍生的巨噬细胞前体细胞中M-CSF和M-CSF-R的表达。肝素介导的LpL细胞解离和动脉LpL基因敲除后，动脉巨噬细胞数量减少。表达LpL的BM的重建补充了主动脉巨噬细胞密度。LpL调节外周血白细胞水平并影响BM单核细胞祖细胞分化和主动脉巨噬细胞积聚。
Tissue macrophages induce and perpetuate pro-inflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride (TG) catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells (WBCs) and BM proliferation, and modulates macrophage retention within the artery. We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL-knockout mice rescued from lethal hypertriglyceridemia within 18 h of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ~40% reduction in blood WBC, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α), master transcription factors (PU.1 and C/EBPα) and colony-stimulating factors (CSFs) and their receptors (CSF-Rs), which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Further, while LpL deficiency was associated with reduced BM uptake and accumulation of TG-rich particles and M-CSF-M-CSF-R binding, TG lipolysis products (e.g., linoleic acid) stimulated expression of M-CSF and M-CSF-R in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density. LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.