Different functions of monocyte subsets in familial hypercholesterolemia: potential function of CD14⁺CD16⁺monocytes in detoxification of oxidized LDL

Abstract

The study was undertaken to investigate whether the two major monocyte subsets defined by the surface markers CD14(+)CD16(+) and CD14(++)CD16(-) show differences in their responses to hypercholesterolemia. Monocytes were rapidly isolated from the blood of hypercholesterolemic, low-density lipoprotein (LDL) receptor-defective familial hypercholesterolemia (FH) patients and from control persons. Using flow cytometry and uptake, adhesion, and phagocytosis assays as well as laser scanning microscopy, we found significant differences between the monocyte subsets. FH-CD14(+)CD16(+) monocytes exhibit an increased uptake of oxidized LDL (oxLDL) via CD36, whereas FH-CD14(++)CD16(-) monocytes preferentially take up native LDL (nLDL). FH-CD14(+)CD16(+) monocytes have an increased expression of surface proteins CD68, stabilin-1, and CD11c and a higher adherence to activated endothelial cells in response to oxLDL and nLDL stimulation. In addition, all CD14(+)CD16(+) monocytes have an increased ability for phagocytosis and a higher resistance to phagocytosis impairment by oxLDL compared with CD14(++)CD16(-) monocytes. We conclude that FH-CD14(+)CD16(+) monocytes have specialized functions in the uptake of oxLDL at activated endothelial cell surfaces, and we hypothesize that these functions are critical for the clearance of oxLDL deposits and apoptotic cells from the vessel wall under hyperlipidemic conditions.

A Novel GGA-Binding Site Is Required for Intracellular Sorting Mediated by Stabilin-1

“…The major activities of stabilin-1-positive cells include control of tissue remodeling and angiogenesis and tolerogenic clearance of non-self and unwanted self products. Our most recent study revealed that stabilin-1 is induced on the CD14 ϩ CD16 ϩ monocyte subset in the blood circulation of patients with proatherosclerotic conditions (20). Our intracellular localization studies demonstrated that stabilin-1 is involved in two intracellular trafficking pathways, receptor-mediated endocytosis and shuttling between the endosomal compartment and trans-Golgi network (TGN) (16).…”

Comparison of gene expression profiles between human and mouse monocyte subsets

“…The difference in lipid ligand-activated PPAR␥ expression and activity and divergent patterns of CD36 expression may suggest particular differences between the species' circulating monocytes in lipid responses. However, potentially arguing in favor of conserved function, despite distinct expression patterns in these pathways, is the preferential uptake of oxidized low-density lipoprotein by CD16 ϩ human monocytes in the context of familial hyperlipidemia 48 and Ly-6C lo mouse monocytes in an experimental model of hypercholesterolemic atherosclerosis. 16 One of the cardinal features of blood monocytes is their phagocytic capacity.…”

Circulating CD14⁺CD16⁺ Monocyte Subsets as Biomarkers of the Severity of Coronary Artery Disease in Patients With Stable Angina Pectoris

“…4 Functionally, CD14 + CD16 -monocytes are professional phagocytes that ingest native low-density lipoprotein (LDL), and generate reactive oxygen species (ROS). 5 In contrast, CD14 + CD16 + monocytes do not generate ROS and are weak phagocytes that preferentially take up oxidized LDL but substantially secrete inflammatory cytokines such as tumor necrosis factor-α after Toll-like receptor-dependent activation by viruses and nucleic acids. 5-7 It was previously reported that CD14 + CD16 + monocytes contribute to CAD, 8 but, to the best of our knowledge, the relationship between the severity of CAD and human monocyte subsets has not yet been examined.…”