Chuchun L Chang1, Itsaso Garcia-Arcos1, Rakel Nyrén1, Gunilla Olivecrona1, Ji Young Kim1, Yunying Hu1, Rishi R Agrawal1, Andrew J Murphy1, Ira J Goldberg2, Richard J Deckelbaum2. 1. From Institute of Human Nutrition (C.L.C., J.Y.K., R.R.A., R.J.D.), Division of Preventive Medicine and Nutrition, Department of Medicine (I.G.-A.), Division of Molecular Medicine, Department of Medicine (Y.H., A.J.M., I.J.G.), and Department of Pediatrics (R.J.D.), College of Physicians and Surgeons, Columbia University, New York; Department of Medical Biosciences/Physiological Chemistry, Umeå University, Sweden (R.N., G.O.); Division of Endocrinology, Diabetes, and Metabolism, New York University School of Medicine, New York (Y.H., I.J.G.); Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.J.M.); and Department of Immunology, Monash University, Melbourne, Victoria, Australia (A.J.M.). 2. From Institute of Human Nutrition (C.L.C., J.Y.K., R.R.A., R.J.D.), Division of Preventive Medicine and Nutrition, Department of Medicine (I.G.-A.), Division of Molecular Medicine, Department of Medicine (Y.H., A.J.M., I.J.G.), and Department of Pediatrics (R.J.D.), College of Physicians and Surgeons, Columbia University, New York; Department of Medical Biosciences/Physiological Chemistry, Umeå University, Sweden (R.N., G.O.); Division of Endocrinology, Diabetes, and Metabolism, New York University School of Medicine, New York (Y.H., I.J.G.); Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (A.J.M.); and Department of Immunology, Monash University, Melbourne, Victoria, Australia (A.J.M.). rjd20@columbia.edu Ira.Goldberg@nyumc.org.
Abstract
OBJECTIVE: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride 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 and BM proliferation and modulates macrophage retention within the artery. APPROACH AND RESULTS: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, 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. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor 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. CONCLUSIONS: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.
OBJECTIVE: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride 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 and BM proliferation and modulates macrophage retention within the artery. APPROACH AND RESULTS: We characterized blood and tissue leukocytes and inflammatory molecules in transgenicLpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficientmice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, 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. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor 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. CONCLUSIONS:LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.
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