Rationale: Tumor necrosis factor receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins for the TNF/interleukin-1/Toll-like receptor superfamily. Ligands of this family comprise multiple important cytokines such as TNF␣, CD40L, and interleukin-1 that promote chronic inflammatory diseases such as atherosclerosis. We recently reported overexpression of TRAF5 in murine and human atheromata and that TRAF5 promotes inflammatory functions of cultured endothelial cells and macrophages.Objective: This study tested the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: Surprisingly, TRAF5؊/؊ /LDLR ؊/؊ mice consuming a high-cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions than did TRAF5 ؉/؉ /LDLR ؊/؊ controls. Plaques of TRAF5-deficient animals contained more lipids and macrophages, whereas smooth muscle cells and collagen remained unchanged. Deficiency of TRAF5 in endothelial cells or in leukocytes enhanced adhesion of inflammatory cells to the endothelium in dynamic adhesion assays in vitro and in murine vessels imaged by intravital microscopy in vivo. TRAF5 deficiency also increased expression of adhesion molecules and chemokines and potentiated macrophage lipid uptake and foam cell formation. These findings coincided with increased activation of JNK and appeared to be independent of TRAF2. Finally, patients with stable or acute coronary heart disease had significantly lower amounts of TRAF5 mRNA in blood compared with healthy controls. Key Words: TRAF5 Ⅲ inflammation Ⅲ atherosclerosis Ⅲ monocyte recruitment Ⅲ foam cells A therosclerosis is one of the leading causes of death worldwide. The concept that inflammatory and immunologic mechanisms drive atherogenesis emerged from both extensive laboratory studies and from clinical observations demonstrating associations between biomarkers of inflammation and cardiovascular events. 1,2 These findings have spurred the quest for antiinflammatory or immunomodulatory treatments to fight atherosclerosis and its sequelae. Selective modulation of key signaling pathways may afford a fruitful strategy to achieve that goal. Conclusions:Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) represent important signal transducers for the TNF/ interleukin (IL)-1/Toll-like receptor (TLR) superfamily, several members of which potently promote atherogenesis. We and others found expression of TRAFs in cells typically resident in the atherosclerotic plaques. [3][4][5][6] However, only a few reports have investigated TRAF-dependent functions in the context of vascular disease: TRAF3 and TRAF2 have been implicated in transducing shear stress, 7,8 and Luo et al recently demonstrated that activation of TNFR2 mediates ischemia-induced atherogenesis by inducing TRAF2-dependent survival pathways. 9 Endothelial cells (ECs) and smooth muscle cells from unstable plaque regions of human carotid arteries overexpress TRAF4. 4 TRAF6 promotes neointima formation on balloon injury in the carotid artery of mice as well as deve...
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...
CD40L figures prominently in atherogenesis. Recent data demonstrate elevated levels of sCD40L in the serum of patients with the metabolic syndrome (MS). This study investigated the role of CD40L in pro-inflammatory gene expression and cellular differentiation in adipose tissue to obtain insight into mechanisms linking the MS with atherosclerosis. Human adipocytes and preadipocytes expressed CD40 but not CD40L. Stimulation with recombinant CD40L or membranes over-expressing CD40L induced a time- and dose-dependent expression of IL-6, MCP-1, IL-8, and PAI-1. Supernatants of CD40L-stimulated adipose cells activated endothelial cells, suggesting a systemic functional relevance of our findings. Neutralising antibodies against CD40L attenuated these effects substantially. Signalling studies revealed the involvement of mitogen-activated protein kinases and NFkB. Furthermore, stimulation with CD40L resulted in enhanced activation of C/EBPa and PPARg and promoted adipogenesis of preadipose cells in the presence and absence of standard adipogenic conditions. Finally, patients suffering from the metabolic syndrome with high levels of sCD40L also displayed high levels of IL-6, in line with the concept that CD40L may induce the expression of inflammatory cytokines in vivo in this population. Our data reveal potent metabolic functions of CD40L aside from its known pivotal pro-inflammatory role within plaques. Our data suggest that CD40L may mediate risk at the interface of metabolic and atherothrombotic disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.