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Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile.

Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A, Seijkens T, Engel D, Cleutjens J, Keller AM, Naik SH, Boon L, Oufella HA, Mallat Z, Ahonen CL, Noelle RJ, de Winther MP, Daemen MJ, Biessen EA, Weber C - J. Exp. Med. (2010)

Bottom Line: The CD40-CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways.Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects.Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6C(high) monocytes, an impaired recruitment of Ly6C(+) monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht 6200 MD, Netherlands. E.Lutgens@path.unimaas.nl

ABSTRACT
The CD40-CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)-deficient (Apoe(-/-)) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40-tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe(-/-) mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6C(high) monocytes, an impaired recruitment of Ly6C(+) monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40-TRAF6, but not CD40-TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40-CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis.

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Role of CD40 in atherosclerosis. (a–c) Apoe−/− mice (n = 19) were fed a normal chow diet for 26 wk and were compared with CD40−/−Apoe−/− (n = 16). Sections of the aortic arch and its main branch points (brachiocephalic artery, right subclavian artery, right carotid artery, left carotid artery, and left subclavian artery) were stained with hematoxylin and eosin (HE; representative sections in a, bottom) to analyze the extent of atherosclerosis (plaque area; a, top left: plaque area aortic arch and branch points; a, top right: en face staining thoraco-abdominal aorta; bars, 2 mm; horizontal bars represent mean) and plaque phenotype (b and c). (b) Macrophage infiltration was expressed as the absolute number of Mac3+ cells per plaque (bars, 100 µm). (c) CD45 and CD3 content were expressed as the percentage of CD3+ or CD45+ cells of all plaque cells (arrows indicate CD45+ cells; bars, 50 µm). Error bars represent mean ± SEM. *, P < 0.05.
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fig1: Role of CD40 in atherosclerosis. (a–c) Apoe−/− mice (n = 19) were fed a normal chow diet for 26 wk and were compared with CD40−/−Apoe−/− (n = 16). Sections of the aortic arch and its main branch points (brachiocephalic artery, right subclavian artery, right carotid artery, left carotid artery, and left subclavian artery) were stained with hematoxylin and eosin (HE; representative sections in a, bottom) to analyze the extent of atherosclerosis (plaque area; a, top left: plaque area aortic arch and branch points; a, top right: en face staining thoraco-abdominal aorta; bars, 2 mm; horizontal bars represent mean) and plaque phenotype (b and c). (b) Macrophage infiltration was expressed as the absolute number of Mac3+ cells per plaque (bars, 100 µm). (c) CD45 and CD3 content were expressed as the percentage of CD3+ or CD45+ cells of all plaque cells (arrows indicate CD45+ cells; bars, 50 µm). Error bars represent mean ± SEM. *, P < 0.05.

Mentions: As in CD40L−/−Apoe−/− mice, deficincy of CD40 reduced the atherosclerotic plaque area in the aortic arch and its branch points, as well as in the thoraco-abdominal aorta (Fig. 1 a). This was associated with a less inflammatory and more fibrotic plaque quality, as reflected by the low amount of thin fibrous cap atheromata (Virmani et al., 2000) that developed in absence of CD40 (Fig. S1 a). The absence of CD40 reduced the lipid core size (ApoE−/−, 35.4% vs. CD40−/−ApoE−/−, 23.3%; P < 0.05), the number of plaque macrophages, and the content of CD45+ cells and CD3+ T lymphocytes (Figs. 1, b and c). The number of Foxp3+ regulatory T cells in plaque or adventitia was unaffected (Fig. S1, b and c). The numbers of cleaved caspase 3+ (apoptotic) cells (Fig. S1 d), as well as the degree of iron or fibrin deposition in the plaque (not depicted), were unaffected.


Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile.

Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A, Seijkens T, Engel D, Cleutjens J, Keller AM, Naik SH, Boon L, Oufella HA, Mallat Z, Ahonen CL, Noelle RJ, de Winther MP, Daemen MJ, Biessen EA, Weber C - J. Exp. Med. (2010)

Role of CD40 in atherosclerosis. (a–c) Apoe−/− mice (n = 19) were fed a normal chow diet for 26 wk and were compared with CD40−/−Apoe−/− (n = 16). Sections of the aortic arch and its main branch points (brachiocephalic artery, right subclavian artery, right carotid artery, left carotid artery, and left subclavian artery) were stained with hematoxylin and eosin (HE; representative sections in a, bottom) to analyze the extent of atherosclerosis (plaque area; a, top left: plaque area aortic arch and branch points; a, top right: en face staining thoraco-abdominal aorta; bars, 2 mm; horizontal bars represent mean) and plaque phenotype (b and c). (b) Macrophage infiltration was expressed as the absolute number of Mac3+ cells per plaque (bars, 100 µm). (c) CD45 and CD3 content were expressed as the percentage of CD3+ or CD45+ cells of all plaque cells (arrows indicate CD45+ cells; bars, 50 µm). Error bars represent mean ± SEM. *, P < 0.05.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822598&req=5

fig1: Role of CD40 in atherosclerosis. (a–c) Apoe−/− mice (n = 19) were fed a normal chow diet for 26 wk and were compared with CD40−/−Apoe−/− (n = 16). Sections of the aortic arch and its main branch points (brachiocephalic artery, right subclavian artery, right carotid artery, left carotid artery, and left subclavian artery) were stained with hematoxylin and eosin (HE; representative sections in a, bottom) to analyze the extent of atherosclerosis (plaque area; a, top left: plaque area aortic arch and branch points; a, top right: en face staining thoraco-abdominal aorta; bars, 2 mm; horizontal bars represent mean) and plaque phenotype (b and c). (b) Macrophage infiltration was expressed as the absolute number of Mac3+ cells per plaque (bars, 100 µm). (c) CD45 and CD3 content were expressed as the percentage of CD3+ or CD45+ cells of all plaque cells (arrows indicate CD45+ cells; bars, 50 µm). Error bars represent mean ± SEM. *, P < 0.05.
Mentions: As in CD40L−/−Apoe−/− mice, deficincy of CD40 reduced the atherosclerotic plaque area in the aortic arch and its branch points, as well as in the thoraco-abdominal aorta (Fig. 1 a). This was associated with a less inflammatory and more fibrotic plaque quality, as reflected by the low amount of thin fibrous cap atheromata (Virmani et al., 2000) that developed in absence of CD40 (Fig. S1 a). The absence of CD40 reduced the lipid core size (ApoE−/−, 35.4% vs. CD40−/−ApoE−/−, 23.3%; P < 0.05), the number of plaque macrophages, and the content of CD45+ cells and CD3+ T lymphocytes (Figs. 1, b and c). The number of Foxp3+ regulatory T cells in plaque or adventitia was unaffected (Fig. S1, b and c). The numbers of cleaved caspase 3+ (apoptotic) cells (Fig. S1 d), as well as the degree of iron or fibrin deposition in the plaque (not depicted), were unaffected.

Bottom Line: The CD40-CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways.Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects.Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6C(high) monocytes, an impaired recruitment of Ly6C(+) monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht 6200 MD, Netherlands. E.Lutgens@path.unimaas.nl

ABSTRACT
The CD40-CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)-deficient (Apoe(-/-)) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40-tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe(-/-) mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6C(high) monocytes, an impaired recruitment of Ly6C(+) monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40-TRAF6, but not CD40-TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40-CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis.

Show MeSH
Related in: MedlinePlus