The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling

Donners, Marjo M. P. C.; Beckers, Linda; Lievens, Dirk; Munnix, Imke C. A.; Heemskerk, Johan W. M.; Janssen, Ben J. A.; Wijnands, Erwin; Cleutjens, Jack P.M.; Zernecke, Alma; Weber, Christian; Ahonen, Cory L.; Benbow, Ulrike; Newby, Andrew C.; Noelle, Randolph J.; Daemen, Mat J.A.P.; Lutgens, Esther

doi:10.1182/blood-2007-05-088906

Cited by 81 publications

(123 citation statements)

References 28 publications

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“…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.…”

Section: Discussionsupporting

confidence: 81%

“…10,11 In accord, Donners et al observed reduced neointima formation and leukocyte infiltration on carotid artery ligation in mice lacking the binding site for TRAF6 on CD40 on leukocytes. 12 The same group recently showed that these mice crossed with Apolipoprotein E-deficient mice develop significantly smaller atherosclerotic lesions on a high-cholesterol diet (HCD). 13 Finally, we recently reported attenuation of atherogenesis in mice deficient for TRAF1.…”

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confidence: 99%

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

Missiou

Rudolf

Stachon

et al. 2010

Circulation Research

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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...

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

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

Missiou

Rudolf

Stachon

et al. 2010

Circulation Research

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“…Previously, we demonstrated that specific deficiency in CD40-TRAF6 signaling, but not CD40-TRAF2/3/5 signaling, in MHCII + cells prevented neointima formation, (22) as well as atherosclerosis, and led to an anti-inflammatory immune profile (21). In atherosclerosis, inactivation of CD40-TRAF6 interactions reduced numbers of circulating Ly6C high monocytes and prevented monocytes from entering the arterial wall.…”

Section: Discussionmentioning

confidence: 99%

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Chatzigeorgiou

Seijkens

Zarzycka

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.

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“…Deficiency or inhibition of CD40L or CD40 in hyperlipidemic (apolipoprotein E [Apoe Ϫ/Ϫ ] or low density lipoprotein receptor [Ldlr Ϫ/Ϫ ]) mice not only reduced the atherosclerotic lesion formation but also resulted in a clinically favorable plaque phenotype featuring extensive fibrosis and only a few inflammatory cells. [5][6][7][8][9][10] Recently, we demonstrated that these phenotypic changes depend on the CD40-TRAF6, but not CD40-TRAF2/ 3/5 axis in leukocytes. 9,10 CD40L is expressed on a plethora of cell types present in or around atherosclerotic plaques, such as T cells, macrophages, smooth muscle cells, and endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

Lievens

Zernecke

Seijkens

et al. 2010

Blood

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255

221

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CD40 ligand (CD40L), identified as a costimulatory molecule expressed on T cells, is also expressed and functional on platelets. We investigated the thrombotic and inflammatory contributions of platelet CD40L in atherosclerosis. Although CD40L-deficient (Cd40l ؊/؊ ) platelets exhibited impaired platelet aggregation and thrombus stability, the effects of platelet CD40L on inflammatory processes in atherosclerosis were more remarkable. Repeated injections of activated Cd40l ؊/؊ platelets into Apoe ؊/؊ mice strongly decreased both platelet and leukocyte adhesion to the endothelium and decreased plasma CCL2 levels compared with wildtype platelets. Moreover, Cd40l ؊/؊ platelets failed to form proinflammatory plateletleukocyte aggregates. Expression of CD40L on platelets was required for plateletinduced atherosclerosis as injection of Cd40l ؊/؊ platelets in contrast to Cd40l ؉/؉ platelets did not promote lesion formation. Remarkably, injection of Cd40l ؉/؉ , but not Cd40l ؊/؊ , platelets transiently decreased the amount of regulatory T cells

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The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling

Cited by 81 publications

References 28 publications

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

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

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis

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