Atherosclerosis is a chronic inflammatory reaction involving both the innate and adaptive immune system. The activation of the adaptive immune system requires the primary stimulus along with the ligation of costimulatory ligands and receptors. Members of the LIGHT/lymphotoxin family of costimulatory molecules are expressed by immune cells that either have been shown to or are thought to influence the development of atherosclerosis as well as on non-immune cells such as hepatocytes. The ligand LIGHT and one of its receptors HVEM have been detected in atherosclerotic plaques and in vitro studies have shown that they have the potential to impact on processes that can influence atherosclerosis development and plaque stability. The proposed study is based upon two major observations in our laboratory (a) overexpression of LIGHT on T-cells increases plasma lipid levels, leads to the accumulation of an HDL1-like particle, and reduces hepatic lipase expression in the liver via a lymphotoxin beta receptor (LTbetaR) dependent pathway and (b) that the transfer of bone marrow from LIGHT transgenic mice (LIGHT-tg) to Western-type diet fed LDLR-/- mice results in the reduction in aortic root atherosclerosis. The goal of this proposal is to understand which LIGHT/lymphotoxin receptors, i.e. LTbetaR or HVEM, and which cells and tissues are involved in the lipid/lipoprotein and atherosclerosis response. Our hypothesis is that signaling via LTbetaR is largely responsible for the lipoprotein effects and that signaling via HVEM is largely responsible for the atherosclerosis effects. Testing this hypothesis will involve examining the effect of global receptor deficiency in knockout mice (aim 1), effect of receptor deficiency in bone marrow derived cells (aim 2), and specific deficiency of LTbetaR in hepatocytes (aim 3) on lipid/lipoprotein metabolism and atherosclerosis. This will be done in the LDLR-/- mouse background and will involve the expression of the ligands LIGHT and lymphotoxin beta at physiological levels and LIGHT overexpression in T cells.
| Getz, Godfrey S; Reardon, Catherine A (2014) The mutual interplay of lipid metabolism and the cells of the immune system in relation to atherosclerosis. Clin Lipidol 9:657-671 |
| Chellan, Bijoy; Koroleva, Ekaterina P; Sontag, Timothy J et al. (2013) LIGHT/TNFSR14 can regulate hepatic lipase expression by hepatocytes independent of T cells and Kupffer cells. PLoS One 8:e54719 |
| Getz, Godfrey S; Reardon, Catherine A (2012) Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol 32:1104-15 |
