Atherosclerosis is a chronic inflammatory disease of elastic and muscular arteries. Early in the pathogenesis of atherosclerosis, aggregated, oxidized lipoprotein particles become attached to proteins in the subendothelial matrix of the affected arteries. Monocytes (Me) that traverse the overlying endothelium come into contact with these matrixbound lipoprotein particles, engulf them, and eventually take up large amounts of lipid, developing into lipid-engorged macrophage (Mf)-derived foam cells. Foam cells accumulate in the lesion, secreting pro-inflammatory cytokines that stimulate further Me influx. When Me enter a site of inflammation, many differentiate into dendritic cells (DC) that pick up antigen and leave the tissue within days to present the antigen to T cells in draining lymph nodes. The remainder differentiate into Mf, which can remain in the tissues for months or years. We hypothesize that interaction of monocytes with aggregated lipoproteins in the extracellular matrix of the arterial wall and with inflammatory cytokines in the environment affect the differentiation and fate of monocytes. Project 2 will determine whether interaction with matrix bound lipoproteins inhibits monocyte migration. Working with these investigators, we will determine whether the atherogenic environment skews the differentiation of Me into less mobile Mf and/or inhibits movement of Me, Mf, and DC so that they remain in the atherogenic environment longer, promoting their uptake of aggregated, oxidized lipoproteins and development into foam cells. Using an in vitro co-culture model with human endothelial cells that has been predictive of Me, Mf, and DC behavior and trafficking in vivo, we have found conditions under which Mf accumulate lipid and take on the phenotype of foam cells. We will determine whether this occurs because interaction of Me with aggregated lipoproteins in the matrix skew their differentiation into sedentary Mf or whether this decreases mobility of DC so they cannot leave (Aim 1). We will determine whether this is mimicked by Me interactions with IL-lb and TNFa, which stimulate the aggregation of lipoproteins in the matrix via secreted sphingomyelinase (Aim 2). We will determine whether IL-6, which has been found in atherosclerotic lesions, promotes the development of foam cells by skewing the differentiation of Me into Mf at the expense of DC (Aim 3). We will determine if agents that promote reverse cholesterol transport or block the actions of the cytokines or their receptors reverse these phenomena.
Showing the most recent 10 out of 21 publications
