Editorial Comment: Stroke and the CD40-CD40 Ligand System: At the Hinge Between Inflammation and Thrombosis
Mounting evidence indicates that procoagulant and inflammatory pathways intertwine in complex networks and that inflammation contributes in an important way to atherogenesis and arterial thrombosis, ultimately leading to diseases such as ischemic stroke. Among the most intriguing recent findings was the detection of an important role of the potent immune mediator CD40 and its counterpart CD40 ligand (CD 154) in thrombosis and atherosclerosis. Initially thought of as solely mediating T lymphocyte–B lymphocyte interactions, CD40 was later also detected on monocytes/macrophages, smooth muscle cells, and endothelial cells. CD40 is an important activation receptor, whose engagement via CD40L endows these cells with powerful functions including the release of proinflammatory cytokines, adhesion receptors, tissue factor, metalloproteinases, and prostaglandins. CD40L, a transmembrane protein structurally related to tumor necrosis factor-α, was initially identified on T lymphocytes. Surprisingly, it was later also detected on platelets. CD40L is rapidly upregulated during platelet activation and triggers an inflammatory response in cells that constitutively express CD40 such as endothelial cells and monocytes/macrophages.1 Thereby activated platelets generate signals for the recruitment of leukocytes to the site of injury and thrombogenesis and can rapidly incite a cascade of inflammation by interacting with cells of the vasculature.
The scenario is more complex as CD40-bearing cells such as endothelial cells, smooth muscle cells, and macrophages also store CD40L that may be used to amplify cell stimulation in an autocrine way.2 And platelets also constitutively express CD40. The binding of CD40L to coexpressed CD40 in a platelet aggregate leads to cleavage of CD40L, resulting in a soluble form of the molecule that is no longer able to elicit an inflammatory response.3 This may represent an effective mechanism to control the inflammatory potential of platelet CD40L in the vascular system.
CD40 and CD40L are both overexpressed in human and experimental atherosclerotic lesions particularly in advanced, rupture-prone, and ruptured plaques.4 CD40/CD40L interaction is associated with increased expression of adhesion molecules, chemokines and cytokines, growth factors, metalloproteinases, and tissue factor in atheroma and thus with mechanisms relevant in plaque rupture and thrombus formation.5 Consequently, inhibition of the CD40/CD40L dyad led to a collagen-rich stable plaque phenotype with less inflammation and lipid content and relatively more collagen and to reduced progression of atherosclerotic lesions.6,7⇓ There is also first evidence that lipid-lowering dietary or medical therapy might positively influence the risk of ischemic complications via lowering the expression of CD40L on experimental atheroma and thereby decreasing tissue factor levels.8
Whereas increased CD40L expression by platelets in acute coronary syndromes had been shown recently, the authors here for the first time provide evidence that the CD40/CD40L system is also activated in acute cerebral ischemia. CD40L expression by platelets, CD40 expression by monocytes, and platelet monocyte aggregates were all increased during acute ischemia as were plasma levels of soluble CD40L. At follow-up after 3 months, increase of CD40L expression and monocyte-platelet aggregates persisted but CD40 expression declined significantly. Potential confounding factors such as infections had been excluded. The authors had investigated 60 patients with acute ischemic stroke, 17 patients with transient ischemic attacks, and a control group of 15 subjects with vascular risk factors and noncerebral vascular diseases. Healthy age- and sex-matched controls were not investigated. Given study results that show an association between CD40-CD40L activation and vascular risk factors, it could be expected that healthy subjects depict particularly low activation levels and thus even stronger differences to patients with acute cerebral ischemia. According to platelet CD40L expression, the authors found no relevant differences between stroke etiologies indicating that CD40-CD40L activation may be among universally active mechanisms shortly before or after ischemia. However, no data are provided regarding stroke etiologies and values in the subacute stage.
The identification of a role of the CD40/CD40L system improves our understanding of the interface between coagulation and inflammation in the pathogenesis of stroke in general. However, this is just the beginning of a new story and many questions now arise rather than being resolved already. Given the fact that most parameters were similarly upregulated in the subacute stage, it is unclear which role this chronically activated system plays in the initiation of cerebral thrombosis and ischemia. Furthermore, it is an interesting question whether platelet CD40L and monocyte-platelet aggregates but also monocytic CD40 in the subacute stage are predictors for recurrent ischemic events. Acute infection was identified as risk or trigger factor of stroke, a phenomenon reflecting the interplay between inflammation and coagulation on a clinical level, and it is of interest whether the CD40/CD40L system may contribute to the pathogenesis of infection-associated stroke that is incompletely understood at present.
Further research on the CD40/CD40L system is of relevance particularly because it is a potential therapeutic target in atherosclerosis and arterial thrombosis.
- ↵Mach F, Schönbeck U, Sukhova G, Bourcier T, Bonnefoy JY, Pober J, Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997; 94: 1931–1936.
- ↵Henn V, Steinbach S, Buchner K, Presek P, Kroczek RA. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood. 2001; 98: 1047–1054.
- ↵Schönbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001; 89: 1092–1103.
- ↵Lutgens E, Cleutjens KBJM, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJAP. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.
- ↵Schönbeck U, Sukhova GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.
- ↵Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT, Libby P. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation. 1999; 100: 1215–1222.