Abstract
Atherosclerosis is the predominant underlying pathology of many types of cardiovascular disease and is one of the leading causes of death worldwide. It is characterized by the retention of oxidized low-density lipoprotein (ox-LDL) in lipid-rich macrophages (foam cells) in the intima of arteries. Autoantigens derived from oxLDL can be used to vaccinate against atherosclerosis. However, a major challenge is the induction of antigen-specific Tregs in a safe and effective way. Here we report that liposomes containing the anionic phospholipid 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) induce Tregs that are specific for the liposomes' cargo. Mechanistically, we show a crucial role for the protein corona that forms on the liposomes in the circulation, as uptake of DSPG-liposomes by antigen-presenting cells is mediated via complement component 1q (C1q) and scavenger receptors (SRs). Vaccination of atherosclerotic mice on a western-type diet with DSPG-liposomes encapsulating an LDL-derived peptide antigen significantly reduced plaque formation by 50% and stabilized the plaques, and reduced serum cholesterol concentrations. These results indicate that DSPG-liposomes have potential as a delivery system in vaccination against atherosclerosis.
Highlights
Atherosclerosis is a disease involving large and medium-sized arteries, which affects millions of people worldwide [1]
While vaccination against atherosclerosis has been successful in murine models [23,24,25,26,27,28], a major challenge is the induction of antigen-specific Regulatory T cell (Treg) in a safe and effective way
OVA323-containing liposomes were prepared with high-Tm lipids, since rigid liposomes have been shown to enhance APC uptake [61] and activation [62], and would, be more potent at inducing T cell responses compared to fluid-state liposomes
Summary
Atherosclerosis is a disease involving large and medium-sized arteries, which affects millions of people worldwide [1]. It is initiated by the retention of LDL in the subendothelial space of arteries, and subsequent oxidation and uptake of LDL (oxLDL) by infiltrating macrophages leading to foam cell formation [2]. It has become clear that atherosclerosis is a chronic inflammatory disease Cells of both the innate and adaptive immune system, such as macrophages, dendritic cells (DCs), T and B lymphocytes, are present in atherosclerotic plaques and are involved in the progression of the disease [3,4].
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