Tumor Necrosis Factor Receptor–Associated Factor 1 (TRAF1) Deficiency Attenuates Atherosclerosis in Mice by Impairing Monocyte Recruitment to the Vessel Wall

Abstract

Background-Members of the tumor necrosis factor superfamily, such as tumor necrosis factor-␣, potently promote atherogenesis in mice and humans. Tumor necrosis factor receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. Methods and Results-This study tested the hypothesis that TRAF1 modulates atherogenesis in vivo. TRAF1Ϫ/Ϫ / LDLR Ϫ/Ϫ mice that consumed a high-cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions than LDLR Ϫ/Ϫ (LDL receptor-deficient) control animals. As the most prominent change in histological composition, plaques of TRAF1-deficient animals contained significantly fewer macrophages. Bone marrow transplantations revealed that TRAF1 deficiency in both hematopoietic and vascular resident cells contributed to the reduction in atherogenesis observed. Mechanistic studies showed that deficiency of TRAF1 in endothelial cells and monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic assays. Impaired adhesion coincided with reduced cell spreading, actin polymerization, and CD29 expression in macrophages, as well as decreased expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in endothelial cells. Small interfering RNA studies in human cells verified these findings. Furthermore, TRAF1 messenger RNA levels were significantly elevated in the blood of patients with acute coronary syndrome. Conclusions-TRAF1 deficiency attenuates atherogenesis in mice, most likely owing to impaired monocyte recruitment to the vessel wall. These data identify TRAF1 as a potential treatment target for atherosclerosis. Key Words: TNF receptor-associated factor 1 Ⅲ inflammation Ⅲ atherosclerosis Ⅲ monocytes A therosclerosis is a chronic inflammatory disease orchestrated by a network of inflammatory cytokines. 1,2 Substantial in vitro and in vivo evidence implicates members of the tumor necrosis factor (TNF) receptor/interleukin (IL)-1/Toll-like receptor superfamily, such as TNF-␣, CD40L, and IL-1␤, in the development of atherosclerosis. 3-5 TNF receptor-associated factors (TRAFs) function as intracellular adaptor proteins that mediate signaling for the TNF/IL-1/Toll-like receptor superfamily by upstream interaction with the respective receptors and consequent activation of downstream signaling molecules. 6,7 Clinical Perspective on p 2044 TRAF1, a 46-kDa molecule, associates with several receptors, including TNFR1, TNFR2, and CD40. According to several studies, TRAF1 functions as an inhibitory protein. 8,9 In contrast to other TRAFs, most resting cells lack TRAF1 but rapidly express TRAF1 on stimulation with TNF-␣, CD40L, lipopolysaccharide, or lymphocyte receptor ligands. 10,11 These data strongly suggest that TRAF1 participates in a negative-feedback loop. Several reports revealed that TRAF1 interferes with TRAF2-dependent nuclear factor-B activation. 12,13 Tsitsikov et al 14 demonstrated enhanced TNF-␣-induced signaling in TRAF1-deficient lymphocytes that co...

TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation

“…Previous reports implicated TRAFs, specifically TRAF1 and -6, with the recruitment of leukocytes to inflamed tissue. [12][13][14] In accord with our data, So et al demonstrated that on induction of an asthma-like response TRAF5 deficiency aggravated airway inflammation. 32 This coincided (just as observed in our study) with enhanced expression of ICAM-1 on TRAF5-deficient ECs.…”

“…23 At the end of the study, mice were harvested and histologically analyzed as described previously. 14,24,25 …”

“…13 Finally, we recently reported attenuation of atherogenesis in mice deficient for TRAF1. 14 These findings suggest that TRAFs participate in vascular disease, but the function of TRAF5 in this context remains unsettled.…”

Molecular Biology of Atherosclerosis

“…Additional details of other TNF family receptor signaling, including IL-1R, TLR4 (similar to TLR2 signaling), and CD40 (similar to TNFR2) are presented in Only a few TRAF proteins have been targeted for knockout to study effects on atherosclerosis. Surprisingly, TRAF1 KO reduced atherosclerosis in LDLR null mice even though TRAF1 had been thought to inhibit TRAF2, particularly in TNFR2 signaling (1217). The apparently pro-atherogenic effect of TRAF1 may possibly be explained by observations on oligomer formation.…”

Overexpression of Tissue Inhibitor of Metalloproteinase 3 in Macrophages Reduces Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice

“…To induce atherosclerosis, 6-week-old male mice were fed a Western diet (15% [w/w] fat and 0.25% [w/w] cholesterol, Research Diets) for 16 (aortic root analysis) or 24 (aorta en face analysis) weeks as previously described. 10,11 …”