HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells

Abstract

HDL cholesterol (HDL-C) plasma levels are inversely related to cardiovascular disease risk. Previous studies have shown in animals and humans that HDL promotes regression of atherosclerosis. We hypothesized that this was related to an ability to promote the loss of monocyte-derived cells (CD68 + , primarily macrophages and macrophage foam cells) from plaques. To test this hypothesis, we used an established model of atherosclerosis regression in which plaque-bearing aortic arches from apolipoprotein E-deficient (apoE −/− ) mice (low HDL-C, high non–HDL-C) were transplanted into recipient mice with differing levels of HDL-C and non–HDL-C: C57BL6 mice (normal HDL-C, low non–HDL-C), apoAI −/− mice (low HDL-C, low non–HDL-C), or apoE −/− mice transgenic for human apoAI (hAI/apoE −/− ; normal HDL-C, high non–HDL-C). Remarkably, despite persistent elevated non–HDL-C in hAI/apoE −/− recipients, plaque CD68 + cell content decreased by >50% by 1 wk after transplantation, whereas there was little change in apoAI −/− recipient mice despite hypolipidemia. The decreased content of plaque CD68 + cells after HDL-C normalization was associated with their emigration and induction of their chemokine receptor CCR7. Furthermore, in CD68 + cells laser-captured from the plaques, normalization of HDL-C led to decreased expression of inflammatory factors and enrichment of markers of the M2 (tissue repair) macrophage state. Again, none of these beneficial changes were observed in the apoAI −/− recipients, suggesting a major requirement for reverse cholesterol transport for the beneficial effects of HDL. Overall, these results establish HDL as a regulator in vivo of the migratory and inflammatory properties of monocyte-derived cells in mouse atherosclerotic plaques, and highlight the phenotypic plasticity of these cells.

Modulation of Macrophage Gene Expression via Liver X Receptor α Serine 198 Phosphorylation

“…However, this regulatory mechanism does not underlie the LXR-dependent induction of CCR7 since depletion of IRF8 had no effect on Ccr7 expression (Pourcet and Pineda-Torra, unpublished). ARG1 is a marker of M2 (antiinflammatory or tissue repair) macrophages, and other accepted M2 markers, such as mannose receptor, are also upregulated in both RAW-LXR␣ S198A (not shown) and regressing plaque macrophages (5,29). This might represent an association of nonphosphorylated LXR␣ S198 with a more reparative M2 macrophage phenotype.…”

“…Thus, our findings suggest that for LXR to induce the expression of Ccr7 it would have to overcome a repressive chromatin environment. We speculate that such a change in chromatin in the CCR7 locus occurs in vivo during atherosclerosis regression, where the phenotypic state of macrophages changes from M1 to M2 upon normalization of hyperlipidemia (5,29,42). Consistent with this idea, treatment of RAW-LXR␣ WT cells with the M2 polarizing cytokine interleukin-4 (IL-4) resulted in the T-and PU.1-dependent induction of Ccr7 mRNA expression (B. Pourcet and I. PinedaTorra, unpublished data).…”

“…This results in the accumulation of cholesterol in the cytoplasm of macrophages, promoting their differentiation into foam cells that become retained in the subendothelial space and contributing to the formation and growth of an atherosclerotic plaque. In some mouse models, normalization of cholesterol levels promotes macrophage emigration from plaques and the regression of atherosclerosis (3)(4)(5)(6). This is mediated in part by the induction of the chemokine receptor CCR7 via LXRs (7).…”

Macrophages and Dendritic Cells

“…119 On reversal of hypercholesterolemia or treatment with statins, the induction of CCR7 in plaque macrophages may promote plaque regression. [120][121][122][123][124][125] Collectively these data suggest that monocyte recruitment and macrophage proliferation, but not macrophage egress, are the key cellular events regulating foam cell lesion progression.…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…Macrophages CD16 + are usually related to a mature M2‐phenotype, also characterized for being positive for CD163 20 a scavenger receptor of the haemoglobin–haptoglobin complex involved in haeme catabolism through a process mediated by regulation of the haeme oxygenase‐1 (HMOX1) expression 79. The presence of CD163 macrophages in human atherosclerotic lesions has been also associated with anti‐inflammatory properties mediated through IL10 21, and studies in mice ApoE −/− models have associated plaque regression with the presence of M2 macrophage expressing CD163 80, 81, 82. Although differentiation of monocytes into macrophages is likely to be terminal, macrophages have the ability to switch phenotype and functional characteristics in response to external signals.…”