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Myeloperoxidase-oxidized LDLs and macrophages.

Myeloperoxidase-oxidized LDLs and  macrophages.

Cardiovascular diseases, the major cause of deaths in western societies and throughout the world are mainly due to atherosclerosis, a chronic inflammatory disease affecting mainly medium and large arteries (WHO, fact sheets of 2015). Local blood flow perturbations or injuries lead to an increased permeability of the endothelial layer, favoring lipoprotein infiltration in the intima where they get oxidized. The oxidized lipoproteins are atherogenic. They activate endothelial cells increasing their chemokine (eg. MCP-1) and cytokine (eg. IL-6) secretion, leading to the recruitment of monocytes that will differentiate into macrophages within the intima. Macrophages become foam cells following internalization of these oxidized LDLs through scavenger receptors. However, most of the studies have focused on copper-oxidized LDLs (Ox-LDLs), while other forms of oxidized LDLs such as myeloperoxidase-oxidized LDLs (MpOx-LDLs) have been neglected while probably more relevant (Boudjeltia et al Mediators Inflamm 2013, ID 750742, 4 pages). Our group has shown that MpOx-LDLs activate different signalling cascades in macrophages compared to Ox-LDLs (Calay D et al, Antioxid Redox Signal 2010, 13:1491-1502). Noteworthy, we have also shown that higher intra-cellular accumulation levels are observed with MpOx-LDLs.

But macrophages are heterogenous. Different signals in the cellular environment functionally activate macrophages, modulating their phenotypes as an adaptive response

-       into M1 or pro-inflammatory macrophages, mainly involved in acute host defense owing to their microbicidal activity

-        or into anti-inflammatory M2 macrophages resolving inflammation by the production of anti-inflammatory mediators

Our group has recently investigated the effects of native or oxidized LDLs on macrophage polarization.

Macrophage polarisation and atherogenesis

We investigated the effect of native or modified LDLs on macrophage polarization, but also on polarized macrophages and on foam cell formation. We compared in particular, the effects of copper-oxidized and myeloperoxidase-oxidized LDLs. To do so, we first validated the use of the RAW 264.7 murine macrophage-like cell line, which is often used to produce foam cells, as a robust and reproducible model for studying macrophage polarization into pro-inflammatory M1 (also named M(LPS+IFNg) according to the “Nomenclature and Experimental Guidelines” about macrophage activation and polarization) and anti-inflammatory M2 (also named M(IL-4+IL-13)) macrophages.

The effects of LDLs on macrophage polarization were investigated by monitoring the expression of M1 and M2 genes following stimulation with native, Ox-LDLs or MpOx-LDLs, in RAW 264.7 cells. Except for MRC1, which is induced only by Ox-LDLs, MpOx-LDLs induced an overexpression of all the selected marker genes at the mRNA level.

MpOx-LDLs also modulate marker gene expression in polarized macrophages, favouring notably anti-inflammatory Arg1 expression in M2 cells, but also in the other phenotypes. Noteworthy, MpOx-LDLs were the most efficient to accumulate lipids intra-cellularly in (un)polarized macrophages whatever the phenotype. These data was largely confirmed in murine bone marrow-derived macrophages.

Our data suggests that MpOx-LDLs were the most efficient to accumulate within cells and to enhance an anti-inflammatory phenotype in M2 cells, but also in the other macrophage phenotypes. These results are presently submitted for publication.