G.H.M. van Puijvelde

Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice.

Atherosclerosis is an inflammatory disease characterized by the influx of macrophages and T cells and IL-17 may connect innate and adaptive immune responses involved in atherogenesis. We investigated the role of IL-17 receptor signaling in atherosclerosis and transplanted LDLr deficient recipient mice with IL-17R deficient bone marrow. Induction of atherosclerosis by Western-type diet induced a 46% reduction in lesion size in the aortic root and the plaque composition revealed no significant changes in collagen content and neutrophil counts, but a reduction in mast cell number and an increase in macrophage number. In addition, we observed a decrease in anti-oxLDL antibodies of the IgG class upon IL-17R BMT, while introduction of IL-17R deficient bone marrow resulted in a reduced IL-6 production and an increased IL-10 production. In conclusion, signaling via the IL-17 receptor in bone marrow derived cells enhances the process of atherosclerosis.

Vaccination against Foxp3(+) regulatory T cells aggravates atherosclerosis.

OBJECTIVE Regulatory T cells are crucial for immune homeostasis and an impaired regulatory T cell function results in many pathological conditions. Regulatory T cells have already been described to be protective in atherosclerosis. However the exact contribution of Foxp3-expressing natural regulatory T cells in atherosclerosis has not been elucidated yet. METHODS AND RESULTS In this study we vaccinated LDL receptor deficient mice with dendritic cells which are transfected with Foxp3 encoding mRNA and studied the effect on initial atherosclerosis. Vaccination against Foxp3 resulted in a reduction of Foxp3(+) regulatory T cells in several organs and in an increase in initial atherosclerotic lesion formation. Furthermore we observed an increase in plaque cellularity and increased T cell proliferation in the Foxp3 vaccinated mice. CONCLUSION We further establish the protective role of Tregs in atherosclerosis. The results illustrate the important role for Foxp3-expressing regulatory T cells in atherosclerosis, thereby providing a potential opportunity for therapeutic intervention against this disease.

Differential effects of regulatory T cells on the initiation and regression of atherosclerosis

OBJECTIVE Regulatory T cells (Tregs) play an important role in the regulation of T cell-mediated immune responses through suppression of T cell proliferation and cytokine production. In atherosclerosis, a chronic autoimmune-like disease, an imbalance between pro-inflammatory cells (Th1/Th2) and anti-inflammatory cells (Tregs) exists. Therefore, increased Treg numbers may be beneficial for patients suffering from atherosclerosis. In the present study, we determined the effect of a vast expansion of Tregs on the initiation and regression of well-established lesions. METHODS AND RESULTS For in vivo Treg expansion, LDL receptor deficient (LDLr(-/-)) mice received repeated intraperitoneal injections of a complex of IL-2 and anti-IL-2 mAb. This resulted in a 10-fold increase in CD4(+)CD25(hi)Foxp3(+) T cells, which potently suppressed effector T cells ex vivo. During initial atherosclerosis, IL-2 complex treatment of LDLr(-/-) mice fed a Western-type diet reduced atherosclerotic lesion formation by 39%. The effect on pre-existing lesions was assessed by combining IL-2 complex treatment with a vigorous lowering of blood lipid levels in LDLr(-/-) mice. This did not induce regression of atherosclerosis, but significantly enhanced lesion stability. CONCLUSION Our data show differential roles for Tregs during atherosclerosis: Tregs suppress inflammatory responses and attenuate initial atherosclerosis development, while during regression Tregs can improve stabilization of the atherosclerotic lesions.

Heat-killed Staphylococcus aureus reduces atherosclerosis by inducing anti-inflammatory macrophages.

Staphylococcus aureus cell wall components can induce IL‐10 responses by immune cells, which may be atheroprotective. Therefore, in this study, we investigated whether heat‐killed S. aureus (HK‐SA) could inhibit the development of atherosclerosis.

Lipocalin-2 contributes to experimental atherosclerosis in a stage-dependent manner

BACKGROUND AND AIMS Lipocalin-2 (Lcn2) is a glycoprotein which can be secreted by immune cells. Several studies in humans have suggested Lcn2 can be used as a biomarker for the detection of unstable atherosclerotic lesions, partly as it is known to interact with MMP-9. METHODS In this study, we generated Ldlr-/-Lcn2-/- mice to assess the functional role of Lcn2 in different stages of atherosclerosis. Atherosclerotic lesions were characterized through histological analysis and myeloid cell populations were examined using flow cytometry. RESULTS We show that Ldlr-/-Lcn2-/- mice developed larger atherosclerotic lesions during earlier stages of atherosclerosis and had increased circulating Ly6Chi inflammatory monocytes compared to Ldlr-/- mice. Advanced atherosclerotic lesions from Ldlr-/-Lcn2-/- mice had decreased necrotic core area, suggesting Lcn2 deficiency may affect lesion stability. Furthermore, MMP-9 activity was diminished in plaques from Ldlr-/-Lcn2-/- mice. CONCLUSIONS Altogether, these findings suggest that Lcn2 deficiency promotes lesion growth in earlier stages of the disease while it decreases MMP-9 activity and necrotic core size in advanced atherosclerosis.