Abstract
Background: Macrophage foam cells (FCs) play a crucial role in the initiation and progression of atherosclerosis. Reducing the formation or inducing the removal of FCs could ameliorate atherosclerosis. The present study examined whether the whole-cell vaccination using FCs could be used as novel prevention and treatment strategies to battle atherosclerosis.Methods: ApoE−/− mice with initial or established atherosclerosis were subcutaneously immunized three times with FCs in Freund's adjuvant.Results: Immunization with FCs resulted in an overt reduction of atherosclerotic lesion in the whole aorta and the aortic root with enhanced lesion stability. Subsequent study in mechanism showed that FCs vaccination dramatically increased CD4+ T cell and CD8+ T cell populations. Immunization with FCs significantly raised the plasma FCs-specific IgG antibodies. Of note, the FCs immune plasma could selectively recognize and bind to FC. FCs immune plasma significantly blocked the process of FCs formation, finally reduced the accumulation of FCs in plaque. Additionally, it was observed that FCs immunization down-regulated the expression level of atherosclerosis related pro-inflammatory cytokines, including IFN-γ, MCP-1, and IL-6 and enhanced the lesion stability with a significant increase in TGF-β1 level and collagen content.Conclusions: These findings demonstrate that the whole-cell vaccination using FCs significantly decreased lesion development and positively modulated lesion progression and stability by targeting FCs. The whole-cell FCs vaccine might represent a potential novel strategy for development of new antibodies and vaccines to the prevention or treatment of atherosclerosis.
Highlights
Atherosclerosis is the most common pathological cause leading to cardiovascular disease which accounts for 17.3 million global deaths per year [1]
To prepare foam cells (FCs), the isolated peritoneal macrophages were cultured with increasing concentrations of oxygenized low density lipoprotein (oxLDL). 50 μg/mL oxLDL was sufficient to lead to the maximal oxLDL uptake by macrophages
Further increase of oxLDL concentration to 100 μg/mL enhanced no significant uptake of oxLDL by macrophages (Figures 1A,B)
Summary
Atherosclerosis is the most common pathological cause leading to cardiovascular disease which accounts for 17.3 million global deaths per year [1]. The complications were mainly caused by the rupture-prone vulnerable plaques [3] In this sense, alternative treatments for atherosclerosis such as immune therapy have come into play [4,5,6]. Atherosclerosis is a chronic inflammatory disease involving accumulated modified lipids (oxygenized low density lipoprotein, oxLDL), macrophages, FCs, dendritic cells, inflamed smooth muscle cells, and endothelial cells [7,8,9]. The circulating monocytes adhere to activated endothelial cells and subsequently migrate into the subendothelial space in response to locally produced chemoattractant molecules. These monocytes further differentiate into macrophages which could take up oxLDL via scavenger receptors [11, 12]. Methods: ApoE−/− mice with initial or established atherosclerosis were subcutaneously immunized three times with FCs in Freund’s adjuvant
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