Toll Receptors in Atherosclerosis

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DESCRIPTION (provided by applicant): Atherosclerosis is not just a simple lipid storage disease. It is now appreciated that atherosclerosis is also a chronic inflammatory disease of the arterial wall. This has been established by studies of specific inflammatory gene deletions in hyperlipidemic mice that influence disease severity. The Toll-like receptors (TLR) of the innate immune system, which sense pathogens and mediate cell activation, can provide an important link between infection, inflammation and atherosclerosis. We discovered that TLR2-mediated inflammation influences disease progression in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic inflammatory TLR2-mediated responses to unknown endogenous agonists are mediated by non bone marrow-derived cells including endothelial cells, smooth muscle cells and adventitial fibroblasts. In contrast the proatherogenic inflammatory responses to the known exogenous, synthetic TLR2 agonist, Pam3, are mediated at least in part by bone marrow-derived cells including macrophages. We will confirm our hypothesis that TLR2-mediated cell activation by either endogenous or exogenous TLR2 agonists is predominately proatherogenic and analyze how TLR2-mediated inflammation influences atherosclerosis. In Aim 1 we will study endogenous agonists of TLR2. We will characterize region-specific expression of TLR2 in vivo in non-bone marrow-derived cells and document the time course of the effect of TLR2 on macrophage infiltration into lesions. We will identify candidate endogenous proatherogenic agonists and define the role of the TLR2 co-receptors, TLR1, TLR6, CD14 and and CD36, in TLR2 signaling. In Aim 2 we will study exogenous agonists of TLR2. We will determine if macrophages are sufficient for mediating proatherogenic inflammation induced by defined exogenous agonists. We will define the role of the TLR2 co-receptors with known exogenous agonists and finally, we will examine if TLR2-mediated signaling participates in disease regression. These studies will enhance our understanding of inflammatory responses in atherosclerosis and potentially identify new TLR targets for therapeutic intervention to reverse or reduce disease risk.