One of the key events in the atherogenic process is the development of foam cells following monocytes-derived macrophage lipid engulfment.,
Following cholesterol deposition, macrophages activate cholesterol removal mechanisms through the interaction of ABCA1 and ABCG1 and apoA-I or HDL.,
This interaction negatively modulates macrophage expression of inflammatory mediators, such as MCP-1 and CD11b,
and inhibits the lymphocyte proliferative response.,
Furthermore, macrophages lacking ABCA1 and/or ABCG1 exhibit an increased lipid raft formation.
The function of the lipid raft is correlated to its cholesterol content and the removal of cholesterol from these micro-domains can interfere with signaling pathways in immune cells,
and with antigen-presenting function.
One main function of lipid rafts is the regulation of signaling through the T cell receptors.–
As an example, the localization of major histocompatibility (MHC) class II molecules in lipid rafts–
facilitate the function of antigen-presenting cells and is essential for T cell activation, as this process decreases the amount of antigen necessary for T cell activation.,
For this reason, cholesterol depletion from lipid rafts can inhibit T cell activation. Both HDL and apoA-I remove cholesterol from lipid rafts via ABCG1, SR-BI and ABCA1, reducing the inflammatory response in macrophages and inhibiting the ability of antigen-presenting cells to stimulate T-lymphocytes.,
Dendritic cells (DCs) are immune cells whose main function is to process an antigen, present it on their surface and activate T-cells. DCs are present in atherosclerotic lesions
and co-localize with T-cells.
DCs produce mediators of the innate immune system and increase the expression of costimulatory molecules, including CD40, CD80 and CD86,,
which are essential for T-cell responses. ApoA-I inhibits DCs differentiation from monocytes, inhibits the ability of DCs to secrete IL-12 when stimulated with anti-CD40 and interferon γ (IFNγ), and increases the production of two inhibitors of DC differentiation, such as IL-10 and PGE2.
Atherosclerotic lesions also contain cells of the adaptive immune system, in particular T cell subsets known to modulate inflammatory process in atherogenesis. BCR and TCR are localized in lipid rafts. In resting cells, BCR and TCR are excluded from lipid rafts. Upon activation, these receptors associate with membrane micro-domains, resulting in a spatial organization of receptor signaling.
The association of BCR and TCR with lipid rafts is dependent on membrane cholesterol content and changes in lipid raft composition and structure induced by HDL or apoA-I can affect receptor activities.,
Both B and T cells egression from lymph nodes is also affected by lysosphingolipids, in particular S1P, a component of HDL.–
S1P carried by HDL positively correlates with HDL-cholesterol, apoA-I, and apoA-II levels. Furthermore, S1P is enriched in small dense subclass 3 of HDL (HDL3
Modulation of S1P1 receptors by a synthetic S1P analogue, FTY720, in LDL-R knockout mice resulted in a marked decrease of peripheral blood lymphocytes, thus preventing their recruitment into sites of inflammation.,
Finally, FTY720 reduces the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitates its release to physiological extracellular acceptors, resulting in decreased cholesterol toxicity in macrophages.
S1P1 is the main S1P receptor involved in the egress of T cells from lymphoid organs ().,
In transgenic mice, S1P1 inhibited the differentiation of regulatory T cells (Tregs) while promoting the development of T helper type 1 (Th1) cells in a reciprocal manner.
We recently showed, in humans, an inverse relation between a HDL and CD3+
Treg cell levels, while no correlation was found between Tregs and LDL cholesterol, total cholesterol or triglyceride levels.
In animal models, other mechanisms by which HDL can modulate Treg have been proposed. ApoA-I administration reduces inflammation in LDL receptor−/−
mice by decreasing the numbers of lymph node immune cells, by increasing Tregs and decreasing the percentage of effector memory T cells.
All these data suggest that some of the effects of HDL on atherosclerosis may result from the modulation of molecules and cells that act as sensors of the immune-inflammatory balance during atherogenesis.
Immune cells and atherosclerosis: effects of HDL and its components.