Hypercholesterolemia links hematopoiesis with atherosclerosis

Abstract

Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized lipoproteins in the growing atheromata and give rise to foam cells, which can then contribute to the necrotic core of lesions. Lipids and leukocytes also interact in other important ways. In experimental models, systemic hypercholesterolemia is associated with severe neutrophilia and monocytosis. Recent evidence indicates that cholesterol-sensing pathways control the proliferation of hematopoietic stem-cell progenitors. Here we review some of the studies that are forging this particular link between metabolism and inflammation, and propose several strategies that could target this axis for the treatment of cardiovascular disease.

Figure 1. Regulating of hematopoietic stem cell proliferation by cholesterol efflux pathways and means of therapeutic intervention

A: Endogenous ApoE bound to proteoglycans or lipid-poor ApoA-I interact with ABCA1 and stimulate cholesterol efflux from hematopoitetic stem cells to form nascent HDL (nHDL) particles. nHDL or plasma HDL (pHDL) can further interact with ABCG1 to enhance cholesterol efflux mechanisms thereby reducing cellular cholesterol levels. The depletion of cellular cholesterol levels results in diminished lipid raft content. As a consequence, inflammatory and proliferative pathways are inhibited, e.g. by reduction of the common beta subunit of the IL3/GM-CSF receptor (IL3Rβ) in lipid rafts. Ultimately these mechanisms slow down proliferation of hematopoietic stem and progenitor cells. B: CCL3 and CXCL8 exert myelosuppressive effects, which are counteracted by CXCL1 or CXCL12. C: Treatment with LXR agonists enhances expression of ApoE, ABCA1, and ABCG1, thus stimulating cholesterol efflux and dampening proliferation of myeloid progenitor cells. Similarly, cholesterol-poor phospholipid/ApoA-I complexes (rHDL) inhibit proliferation of myeloid progenitor cells. Red arrows indicate mechanisms of myelosuppressive capacities, whereas green arrows indicate myeloproliferative effects. Modified from [39].

Figure 2. Regulating of hematopoietic stem cell mobilization by cholesterol efflux pathways

Macrophages and dendritic cells in the spleen secrete IL23, which in turn promotes IL17 production in Th17 cells. IL17 drives G-CSF secretion which shifts granulocyte-monocyte-progenitor (GMP) commitment towards neutrophils. Neutrophils create a protease-rich environment in the bone marrow allowing for cleavage of CXCR4 on hematopoietic stem and progenitor cells (HSPCs) thus facilitating the exit from the bone marrow. In parallel, decreases in CXCL12-secreting osteoblasts or nestin+ mesenchymal stem cells ease HSPC bone marrow exit and consequently extramedullary hematopoiesis. In another mechanism, senescent neutrophils are cleared by macrophages, a process that represses the IL23 secretion from macrophages. LXR agonists enhance Gas6 and Mer expression on macrophages, hence promoting clearance of phosphatidylserine (PS)-expressing neutrophils and repressing IL23 secretion. Modified from [100].