Directing TRAF-ic

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The recognition that atherosclerosis is a chronic inflammatory disease has emphasized the fundamental link between the innate immune system and disease pathogenesis. Atherosclerotic lesions develop at vulnerable locations throughout the vasculature as a result of detection of endogenous or microbial ligands by germ-line encoded pattern recognition receptors, including the innate immune Toll-like receptors (TLRs).1,2 Certain dietary lipids that contribute to atherosclerotic disease resemble on a molecular level lipids expressed in the microbial cell wall and are recognized by TLRs. Engagement via TLRs of dietary lipid molecules on both immune and nonimmune cells initiates inflammatory responses that persist chronically and culminate in the deposition of fatty streaks, which progress to occlusive atherosclerotic plaques.3 Article see p 1739 The vascular endothelium is central in the initial cellular and molecular responses to not only infection and tissue injury, but also to overly abundant dietary lipids. Vascular endothelial cells express TLRs, and a fundamental event in the initiation of atherosclerosis is the upregulation of adhesion molecules on endothelial cells that promote localized and restricted recruitment of circulating leukocytes and platelets that support leukocyte tethering and rolling, firm adhesion, and transmigration into underlying tissues. This amassing of cells contributes to the composition of the atherosclerotic lesion. In addition to the induction of adhesion molecule expression, dietary lipids can also incite the production of inflammatory cytokines by endothelial cells, which act in an autocrine and paracrine manner to feed the inflammatory response. Innate immune activation of hematopoietic cells, most notably monocytes and macrophages, is another central response that leads to the development of chronic atherosclerotic disease. Monocytes and macrophages express TLRs that respond to microbes and dietary lipids in much the same manner as endothelial cells, although the outcome of TLR signaling differs as a result of cell-specific functions. Activated macrophages secrete …