Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice

Schönbeck, Uwe; Sukhova, Galina K.; Shimizu, K; Mach, François; Libby, Peter

doi:10.1073/pnas.97.13.7458

Cited by 319 publications

(238 citation statements)

References 58 publications

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“…It is now established that this pathway, in addition to playing an essential role in cellular immunity as traditionally acknowledged, is a key component of the pathophysiology of multiple inflammatory disorders, including vascular inflammation (14, 43, 44), which is dependent on the integrated signaling pathways of CD40 and TNF-␣. This integration has been confirmed in murine models, where inhibition of CD40 signaling decreases inflammatory infiltrates in established atherosclerotic lesions (45) and TNF-␣ blockade reduces progression of atherosclerosis (46). A recent but growing body of evidence indicates that vascular inflammation is also an important component of IBD pathogenesis (47).…”

Section: Discussionmentioning

confidence: 66%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

154

101

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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

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Section: Discussionmentioning

confidence: 66%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

154

101

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“…These include TXA2, a costimulator of platelets that has vasoconstrictive activity; P-selectin, an ␣-granule protein that mediates platelet rolling, leukocyte adhesion, and coagulation; ADP and serotonin, which amplify platelet aggregation; platelet-derived growth factor, a growth factor for vascular cells; and CD40L, a member of the tumor necrosis factor-␣ family of proteins (reviewed in Gresele et al 4 ). Although any of these factors could contribute to long-term vascular pathologies, CD40L appears to be particularly relevant because this protein is now known to be prothrombotic 5 and proinflammatory, to have a proven role in atherosclerotic lesion progression, 6 and to be a risk factor for cardiovascular events. 7 CD40 ligand (CD40L, CD154, gp39) was originally identified in T lymphocytes, where it has a role in the immune response by binding to its receptor on B cells, CD40 (reviewed in Schonbeck and Libby 8 ).…”

mentioning

confidence: 99%

Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation

2003

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Background-Glycoprotein (GP) IIb/IIIa antagonists inhibit platelet aggregation, an activity attributed to the clinical benefits of these drugs in settings that involve acute coronary thrombosis. However, platelet activation and subsequent aggregation are now known to cause the release of a soluble form of CD40 ligand (sCD40L), a prothrombotic and proinflammatory protein with GP IIb/IIIa binding activity and an established role in atherosclerotic lesion progression. The present study was designed to determine what effect GP IIb/IIIa antagonists have on the release of sCD40L. Methods and Results-Doses of eptifibatide, abciximab, and tirofiban that inhibited platelet aggregation by at least 80% also inhibited sCD40L release in vitro (by 85%, 57%, and 80%, respectively). When platelets were stimulated with a thrombin receptor agonist, inhibition by GP IIb/IIIa antagonists occurred without affecting the release of ␤TG, an ␣-granule protein. Unexpectedly, concentrations of the 3 antagonists that blocked aggregation by only 20% to 50% potentiated the release of sCD40L (by 19% to 26%). Platelets from aspirin-treated individuals were partially protected from sCD40L release, but only when the agonist was collagen, an affect augmented by the addition of GP IIb/IIIa antagonists. Conclusions-These studies suggest that the mechanisms responsible for the clinical benefits of GP IIb/IIIa antagonists (at doses that optimally inhibit aggregation) and of aspirin may not be limited to the inhibition of thrombosis through their blockade of platelet aggregation but may also involve the inhibition of inflammation and thrombosis through their blockade of sCD40L release. These studies also provide a mechanism by which suboptimal doses of GP IIb/IIIa antagonists may be proinflammatory. . Arterial thrombosis in these settings is dependent on platelet aggregation, a process mediated by the binding of soluble fibrinogen to GP IIb/IIIa on the surface of stimulated platelets. GP IIb/IIIa antagonists are effective in these indications because they block the binding of soluble fibrinogen to GP IIb/IIIa and therefore inhibit platelet aggregation. Interestingly, some trials suggest less accrual of events such as myocardial infarction and death in the treatment arm than are observed in the placebo arm during the year after an event. Thus, the clinical benefit extends well past the time of acute administration of GP IIb/IIIa antagonists, which is often less than 20 hours. 2,3 Although it has been considered that thrombosis-mediated ischemia is a culprit for long-term negative consequences, including atherosclerotic lesion progression after acute arterial coronary thrombosis, it is also possible that thrombosis itself could generate such factors, which could be blocked by GP IIb/IIIa antagonists.Platelet stimulation and subsequent aggregation are known to cause the expression or release of several factors that could affect vascular pathology. These include TXA2, a costimulator of platelets that has vasoconstrictive activity; P-selectin, an ␣-granule...

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“…In situ analysis of human atherosclerotic lesions revealed the co-expression of CD154 and CD40 on vascular endothelium and smooth muscle cells (15). Blockade of CD40-CD154 interaction in atherosclerosis was found not only to diminish the formation and progression of mouse atheroma but also to foster changes in lesions associated with plaque destabilization (16,17). Recently, it has also been shown that the engagement of CD40 on endothelial cells by CD154 induces in vitro vessel-like tubule formation and expression of matrix metalloproteinases, two events involved in neovascularization (18).…”

mentioning

confidence: 99%

CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis

Deregibus

Buttiglieri

Russo

et al. 2003

Journal of Biological Chemistry

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CD40 has been involved in tumor and inflammatory neoangiogenesis. In this study we determined that stimulation of endothelial CD40 with sCD154 induced resistance to apoptosis and in vitro vessel-like formation by human microvascular endothelial cells (HMEC). These effects were determined to be mediated by CD40-dependent signaling because they were inhibited by a soluble CD40-muIg fusion protein. Moreover, apoptosis of HMEC was associated with an impairment of Akt phosphorylation, which was restored by stimulation with sCD154. The anti-apoptotic effect as well as in vitro vessel-like formation and Akt phosphorylation were inhibited by treatment of HMEC with two unrelated pharmacological inhibitors of phosphatidylinositol 3-kinase (PI3K), wortmannin and LY294002. CD40 stimulation induced a rapid increase in Akt enzymatic activity that was not prevented by cycloheximide, an inhibitor of protein synthesis. The enhanced Akt activity induced by stimulation of endothelial CD40 was temporarily correlated with the association of CD40 with TRAF6, c-Cbl, and the p85 subunit of PI3K. Expression of negativedominant Akt inhibited the activation of endogenous Akt through CD40 stimulation, despite the observation that association of CD40 with TRAF6, c-Cbl, and PI3K was intact. The defective activation of Akt abrogated not only the anti-apoptotic effect of CD40 stimulation but also the proliferative response, the enhanced motility, and the in vitro formation of vessel-like tubular structures by CD40-stimulated HMEC. In conclusion, these results suggest that endothelial CD40, through activation of the PI3K/Akt signaling pathway, regulates cell survival, proliferation, migration, and vessel-like structure formation, all steps considered critical for angiogenesis.CD40 is a member of the tumor necrosis factor (TNF) 1 receptor superfamily, which provides activation signals in antigen-presenting cells such as B cells, macrophages, and dendritic cells (1, 2). Among the molecular mechanisms that link immunity to inflammation, the interaction between CD40 and its counterreceptor CD154 has rapidly emerged as a key system in the regulation of vascular pathophysiological processes such as atherogenesis (3, 4), tumor neoangiogenesis (5, 6), and inflammation (2, 8). Under physiological conditions, CD40 is expressed at low levels on endothelial cells but is up-regulated in areas of inflammation (9). Ligation of endothelial CD40 by CD154, either expressed on activated monocytes or T cells (2) or disgorged by platelets upon activation (10), induces production of various inflammatory cytokines and chemokines, procoagulant activity, adhesion molecules, metalloproteinases, and inflammatory mediators (11-14). These mediators have been implicated in the development and progression of atherosclerosis. In situ analysis of human atherosclerotic lesions revealed the co-expression of CD154 and CD40 on vascular endothelium and smooth muscle cells (15). Blockade of CD40-CD154 interaction in atherosclerosis was found not only to diminish the formation and pr...

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Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice

Cited by 319 publications

References 58 publications

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation

CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis

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