Abstract 3962: TRAF-1 Deficiency Attenuates Atherosclerosis in Mice by Impairing Monocyte Recruitment to the Vessel Wall
Background: Members of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFalpha, and IL-1beta potently promote atherogenesis in mice and likely also in humans. TNF receptor associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. We recently reported over-expression of TRAFs in murine and human atheromata and demonstrated dependency of classic inflammatory functions on TRAFs in endothelial cells and macrophages. Here we test the hypothesis that TRAF-1 modulates atherogenesis in vivo.
Methods and Results: TRAF-1–/LDLR– mice fed a high cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR– controls. Intimal lesion size decreased by up to 56±6% and 33±5% in sections of the aortic arch and aortic root, respectively (n>10 per group, P<0.01 each). Plaques of TRAF-1-deficient animals contained up to 46±9% and 55±4% fewer macrophages while smooth muscle cell content increased by up to 32±6 and 36±7%, characteristics associated with non disrupted plaques in humans. Lipid content, collagen content, and lymphocyte content remained unchanged. In vitro, gene expression profiling revealed reduced expression of adhesion molecules (VCAM-1, ICAM-1), chemokines (CCL2, CXCL2), and growth factors (M-CSF) in TRAF-1-deficient endothelial cells as well as of integrins (CD29, CD11b) and chemokines/chemokine receptors (CXCL2, CCR1) in TRAF-1-deficient macrophages, verified by siRNA studies in human cells. Finally, both deficiency of TRAF-1 in endothelial cells and neutrophils/monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic adhesion assays.
Conclusions: We present the novel finding that TRAF 1 deficiency attenuates atherogenesis in mice, an effect most likely mediated by impaired monocyte recruitment to the vessel wall. These data identify TRAF-1 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.