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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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Deficiency of CD40 induces plaque fibrosis. Sections of the aortic arch and its main branch points (brachiocephalic artery, right and left subclavian artery, and right and left carotid artery) of Apoe−/− mice (n = 19) and CD40−/−Apoe−/− (n = 16) mice fed a normal chow diet for 26 wk were stained for α-SMA to detect the content of SMCs (a, representative sections on the left; bars, 50 µm), which was quantified as the percentage of α-SMA–positive plaque area (a, right). (b and c) Consecutive sections were stained with Sirius red to assess the content of collagen in the plaque by light (b) and polarized light (c) microscopy (representative sections on the left; bars, 50 µm). In addition, the content of collagen was expressed as the percentage of α-SMA–positive plaque area (b, right) and the color spectrum obtained using polarization microscopy was analyzed (c, right). (d and e) The content of collagen I (d) and collagen III (e) was assessed by immunohistochemistry (representative sections on the left; bars, 100 µm) and expressed as the percentage of positively stained plaque area (right). Error bars represent mean ± SEM. *, P < 0.05.
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fig2: Deficiency of CD40 induces plaque fibrosis. Sections of the aortic arch and its main branch points (brachiocephalic artery, right and left subclavian artery, and right and left carotid artery) of Apoe−/− mice (n = 19) and CD40−/−Apoe−/− (n = 16) mice fed a normal chow diet for 26 wk were stained for α-SMA to detect the content of SMCs (a, representative sections on the left; bars, 50 µm), which was quantified as the percentage of α-SMA–positive plaque area (a, right). (b and c) Consecutive sections were stained with Sirius red to assess the content of collagen in the plaque by light (b) and polarized light (c) microscopy (representative sections on the left; bars, 50 µm). In addition, the content of collagen was expressed as the percentage of α-SMA–positive plaque area (b, right) and the color spectrum obtained using polarization microscopy was analyzed (c, right). (d and e) The content of collagen I (d) and collagen III (e) was assessed by immunohistochemistry (representative sections on the left; bars, 100 µm) and expressed as the percentage of positively stained plaque area (right). Error bars represent mean ± SEM. *, P < 0.05.

Mentions: Besides the decrease in inflammatory cell content, plaques of CD40−/−Apoe−/− mice had a more fibrotic appearance. The content of α–smooth muscle actin (SMA; α-SMA+ cells; Fig. 2 a) and collagen (Fig. 2 b) was significantly increased. Bright-field polarization microscopy revealed that in the absence of CD40, the color distribution of the collagen deviated toward the red spectrum, indicating larger collagen fibrils (MacKenna and Omens, 1996). Concordant with these findings, we found an increase in the amount of collagen I and III in the plaque (Fig. 2, d and e).


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)

Deficiency of CD40 induces plaque fibrosis. Sections of the aortic arch and its main branch points (brachiocephalic artery, right and left subclavian artery, and right and left carotid artery) of Apoe−/− mice (n = 19) and CD40−/−Apoe−/− (n = 16) mice fed a normal chow diet for 26 wk were stained for α-SMA to detect the content of SMCs (a, representative sections on the left; bars, 50 µm), which was quantified as the percentage of α-SMA–positive plaque area (a, right). (b and c) Consecutive sections were stained with Sirius red to assess the content of collagen in the plaque by light (b) and polarized light (c) microscopy (representative sections on the left; bars, 50 µm). In addition, the content of collagen was expressed as the percentage of α-SMA–positive plaque area (b, right) and the color spectrum obtained using polarization microscopy was analyzed (c, right). (d and e) The content of collagen I (d) and collagen III (e) was assessed by immunohistochemistry (representative sections on the left; bars, 100 µm) and expressed as the percentage of positively stained plaque area (right). 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

fig2: Deficiency of CD40 induces plaque fibrosis. Sections of the aortic arch and its main branch points (brachiocephalic artery, right and left subclavian artery, and right and left carotid artery) of Apoe−/− mice (n = 19) and CD40−/−Apoe−/− (n = 16) mice fed a normal chow diet for 26 wk were stained for α-SMA to detect the content of SMCs (a, representative sections on the left; bars, 50 µm), which was quantified as the percentage of α-SMA–positive plaque area (a, right). (b and c) Consecutive sections were stained with Sirius red to assess the content of collagen in the plaque by light (b) and polarized light (c) microscopy (representative sections on the left; bars, 50 µm). In addition, the content of collagen was expressed as the percentage of α-SMA–positive plaque area (b, right) and the color spectrum obtained using polarization microscopy was analyzed (c, right). (d and e) The content of collagen I (d) and collagen III (e) was assessed by immunohistochemistry (representative sections on the left; bars, 100 µm) and expressed as the percentage of positively stained plaque area (right). Error bars represent mean ± SEM. *, P < 0.05.
Mentions: Besides the decrease in inflammatory cell content, plaques of CD40−/−Apoe−/− mice had a more fibrotic appearance. The content of α–smooth muscle actin (SMA; α-SMA+ cells; Fig. 2 a) and collagen (Fig. 2 b) was significantly increased. Bright-field polarization microscopy revealed that in the absence of CD40, the color distribution of the collagen deviated toward the red spectrum, indicating larger collagen fibrils (MacKenna and Omens, 1996). Concordant with these findings, we found an increase in the amount of collagen I and III in the plaque (Fig. 2, d and e).

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