Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.

Elevated leukocyte cell numbers (leukocytosis), and monocytes in particular, promote atherosclerosis; however, how they become increased is poorly understood. Mice deficient in the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which promote cholesterol efflux from macrophages and suppress atherosclerosis in hypercholesterolemic mice, displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing Lin − Sca-1 + Kit + (LSK) in the bone marrow.

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe -/-mice fed a chow or Western-type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1 -/-mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1-and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe -/-mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.

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Abstract-Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries, but the mechanisms linking cholesterol accumulation in macrophage foam cells to inflammation are poorly understood. Macrophage cholesterol efflux occurs at all stages of atherosclerosis and protects cells from free cholesterol and oxysterol-induced toxicity. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of macrophage cholesterol efflux to serum or HDL in macrophage foam cells, but other less efficient pathways such as passive efflux are also involved. 5 and combined deficiency of these transporters in bone marrow-derived hematopoietic cells leads to severe defects in cholesterol efflux to HDL, massive cholesteryl ester accumulation in macrophages, and accelerated atherogenesis in a susceptible background. 6,7 In addition, by modulating cholesterol homeostasis, ABCA1 and ABCG1 may be central to the antiapoptotic and antiinflammatory effects of HDL. 4,8,9 Cholesterol accumulation in the plasma membrane of Abca1 Ϫ/Ϫ and Abcg1 Ϫ/Ϫ macrophages has been shown to increase signaling of Tolllike receptors enhancing the inflammatory response to LPS or other TLR ligands. 10 -13 As a consequence, mice lacking ABCA1 and ABCG1 accumulate prominent macrophage foam cells in various tissues such as in the lung, liver, spleen, or thymus, 6,14 -17 and in response to an inflammatory stimulus Abcg1 Ϫ/Ϫ bone marrow transplanted mice revealed a profound inflammatory infiltrate in the adventitia and necrotic core region of atherosclerotic lesions. 13 ABC Transporters and Active Cholesterol EffluxAlthough passive cholesterol diffusion accounts for a large part of the efflux of cholesterol from nonloaded macrophages, active cholesterol efflux from macrophage foam cells via ABCA1 and ABCG1 represents as much as 70% of the total cellular cholesterol efflux following cholesterol loading. 6,7,18,19 ABCA1 and Cholesterol Efflux to ApoA-I Two distinct mechanisms have been proposed to explain ABCA1-mediated cholesterol efflux from macrophage to apoA-I. One is that apoA-I forms complexes with phospholipid and cholesterol at the cell surface in a process promoted by ABCA1 activity. 20,21 There is abundant evidence that ABCA1-mediated cholesterol efflux to apoA-I can occur at the plasma membrane. [22][23][24] The other is that apoA-I binds ABCA1 at the cell surface and is subsequently internalized and targeted to late endosomes, where apoA-I picks up lipids helps to integrate these findings by showing that apoA-1 stabilizes ABCA1 against calpain proteolysis after internalization of ABCA1. Although these mechanisms are not mutually exclusive, there is controversy as to which mechanism plays the dominant role in ABCA1-mediated cholesterol efflux from macrophages to apoA-I. Recent studies have confirmed internalization of apoA-I and its accumulation in the late endosome/lysosome compartments in ABCA1-expressing macrophages. 30 -32 These studies also showed that the majority of the resec...