Hypercholesterolemia promotes bone marrow cell mobilization by perturbing the SDF-1: CXCR4 axis

AL Gomes, T Carvalho, J Serpa… - Blood, The Journal of …, 2010 - ashpublications.org
AL Gomes, T Carvalho, J Serpa, C Torre, S Dias
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
Hypercholesterolemia is associated with elevated peripheral blood leukocytes and
increased platelet levels, generally attributed to cholesterol-induced proinflammatory
cytokines. Bone marrow (BM) cell mobilization and platelet production is achieved by
disrupting the SDF-1: CXCR4 axis, namely with granulocyte colony-stimulating factor and/or
CXCR4 antagonists. Here we show that high cholesterol disrupts the BM SDF-1: CXCR4
axis; promotes the mobilization of B cells, neutrophils, and progenitor cells (HPCs); and …
Abstract
Hypercholesterolemia is associated with elevated peripheral blood leukocytes and increased platelet levels, generally attributed to cholesterol-induced proinflammatory cytokines. Bone marrow (BM) cell mobilization and platelet production is achieved by disrupting the SDF-1:CXCR4 axis, namely with granulocyte colony-stimulating factor and/or CXCR4 antagonists. Here we show that high cholesterol disrupts the BM SDF-1:CXCR4 axis; promotes the mobilization of B cells, neutrophils, and progenitor cells (HPCs); and creates thrombocytosis. Hypercholesterolemia was achieved after a 30-day high-cholesterol feeding trial, resulting in elevated low-density lipoprotein (LDL) cholesterol levels and inversion of the LDL to high-density lipoprotein cholesterol ratio. Hypercholesterolemic mice displayed lymphocytosis, increased neutrophils, HPCs, and thrombocytosis with a lineage-specific decrease in the BM. Histologic analysis revealed that megakaryocyte numbers remained unaltered but, in high-cholesterol mice, they formed large clusters in contact with BM vessels. In vitro, LDL induced stromal cell–derived factor-1 (SDF-1) production, suggesting that megakaryocyte delocalization resulted from an altered SDF-1 gradient. LDL also stimulated B cells and HPC migration toward SDF-1, which was blocked by scavenger receptor class B type I (cholesterol receptor) inhibition. Accordingly, hypercholesterolemic mice had increased peripheral blood SDF-1 levels, increased platelets, CXCR4-positive B lymphocytes, neutrophils, and HPCs. High cholesterol interferes with the BM SDF-1:CXCR4 axis, resulting in lymphocytosis, thrombocytosis, and HPC mobilization.
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