Maturation of dendritic cells is involved in the progression of atherosclerosis in ApoE-deficient mice

Abstract

Purpose: Inflammation promotes plaque progression in atherosclerosis. Dendritic cells (DC) play a crucial role in the regulation of the immune system. However, the effect of DCs on immune response depends on their maturation state, with mature DCs enhancing and immature DCs attenuating the inflammatory process. We investigated the effects of MCS-18, which inhibits DC maturation, on the progression of atherosclerosis in ApoE-deficient mice. Methods: ApoE-deficient mice were fed a Western-type diet (n=32) or normal chow (control group; n=16) for 12 weeks. MCS-18 (500μg/kg body weight, n=16) or saline (n=16) was given twice a week during the time period of Western-type diet. After 12 weeks, blood was collected from anesthetized animals by cardiac puncture. Mice were perfused transcardially, whereafter the aortic arch was isolated. Flow cytometry was used to quantify mature DCs (lin-CD11c+HLA-DR+CD80+/CD83+/CD86+) and regulatory T cells (CD4+CD25+Foxp3+) in the spleen. Plaque size of the aortic arch was evaluated by enface staining. Luminex-based assays served to detect concentrations of 32 inflammatory cytokines and chemokines in serum. Results: Induced atherosclerosis led to a significant increase in the expression of co-stimulatory molecules on DCs (CD80+DCs: p<0.05; CD83+DCs: p<0.001; CD86+DCs: p<0.01) in the spleen when compared to the control group, which points towards an induction of DC-maturation in the atherosclerotic mice. The application of MCS-18 significantly suppressed this increase. Apart from that, the percentage of splenic Tregs was significantly increased after application of MCS-18 when compared to placebo-treated atherosclerotic mice (8.7% vs. 11.6% of CD4+ T cells, p<0.01). With regard to plaque size, MCS-18 significantly reduced percent plaque area in the aortic arch 14.33% vs. 7.23%, p<0.001). Finally, atherosclerosis caused an increase in 20 of the 32 investigated inflammatory cytokines and chemokines in serum. MCS-18 suppressed the increase in 14 of these inflammatory markers, in particular IFN-y, IL-12, MCP-1, and CXCL-9. Conclusion: The results of our study suggest that the maturation of DCs plays a crucial role in experimental atherosclerosis. The inhibition of maturation by MCS-18 seems to be associated with its preventive effects on plaque progression, presumably by suppressing the inflammatory response.