Monocyte to macrophage differentiation and plasticity in dyslipidaemia

Abstract

Dyslipidaemia is only treated in the context of cardiovascular disease. However, a high residual risk of cardiovascular clinical events remains after lipid-lowering treatments.

Monocytes and macrophages directly interact with lipids in the circulation and the atherosclerotic plaque. These interactions may reveal pro-atherogenic pathways not targeted. Macrophages are susceptible to microenvironmental factors, which induce inflammatory phenotypes associating with unstable plaques or anti-inflammatory phenotypes promoting plaque stabilisation. Whether lipids modulate macrophage inflammatory profile is important to determine. As macrophages derive from monocytes, monocyte phenotype may also be important.

Monocytes were differentiated into macrophages and inflammatory surface markers and cytokine production analysed by flow cytometry.

The inflammatory profile of monocytes did not direct that of the differentiated macrophages, either in an individual’s own biological conditions, or intrinsically when individual serum factors were removed. The propensity for macrophages to respond to inflammatory stimuli (LPS+IFN) was not enhanced, nor plasticity to anti-inflammatory polarisation (IL-4+IL-13) restricted, in people with inflammatory monocytes. Inflammatory macrophage markers associated with lipid levels (ApoA1, oxLDL, triglycerides, LDL particle size). Only oxLDL associated with monocyte phenotype. The in vitro experiment found that continuous oxLDL exposure increases macrophage production of some inflammatory cytokines and skews surface marker expression. This may be related to oxLDL uptake, with increased CD36 expression.

We found that individuals’ macrophages have a unique capacity to respond to both inflammatory and anti-inflammatory stimuli, with correlations in levels of multiple cytokines. The results propose that macrophage phenotype is plastic to polarisation by factors in an atherosclerotic plaque, irrespective of the monocyte phenotype from which they derive.