Phenotypic modulation of macrophages in response to plaque lipids

Abstract

Purpose of review: The accumulation of macrophages in the vascular wall is a hallmark of atherosclerosis. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition, and stability. In atherosclerotic plaques, macrophages encounter a microenvironment that comprises a variety of lipid oxidation products, each of which has diverse biological effects. In this review, we summarize recent advances in our understanding of the effects of plaque lipids on macrophage phenotypic polarization.

Recent findings: Atherosclerotic lesions in mice and in humans contain various macrophage phenotypes, which play different roles in mediating inflammation, the clearance of dead cells, and possibly resolution. Macrophages alter their phenotype and biological function in response to plaque lipids through the upregulation of specific sets of genes. Interaction of oxidized lipids with pattern recognition receptors and activation of the inflammasome by cholesterol crystals drive macrophages toward an inflammatory M1 phenotype. A new phenotype, Mox, develops when oxidized phospholipids activate stress response genes via Nrf2. Other lipid mediators such as nitrosylated-fatty acids and omega-3 fatty acid-derived products polarize plaque macrophages toward anti-inflammatory and proresolving phenotypes.

Summary: A deeper understanding of how lipids that accumulate in atherosclerotic plaques affect macrophage phenotype and function and thus atherosclerotic lesion development and stability will help to devise novel strategies for intervention.

Figure 1

Modulation of macrophage phenotype and function occurs during the progression and resolution of inflammation. In atherosclerosis, phenotypic polarization of macrophages is affected by bioactive plaque lipids. In a simple model, saturated fatty acids (SFA), oxidized cholesteryl esters (OxCE), and oxidized phospholipids (OxPL) induce inflammatory gene expression via scavenger receptor CD36, toll-like receptors (TLR), and NFκB activation, as seen in M1 macrophages. Crystallized cholesterol activates the NLRP3 inflammasome to sustain inflammation, and lysophospholipids (LysoPL) act on the G-protein coupled receptor G2A. Some macrophages are transformed by oxidized lipid signaling via Nrf2 into Mox macrophages. Other bioactive lipids such as nitrosylated fatty acids (NO-FA), sphingosine-1-phosphate (S1P), and oxysterols activate PPARγ, sphingosine-1-phosphate receptors, and liver X receptors (LXR), respectively, to modulate towards an anti-inflammatory M2 phenotype. However, oxysterols can also induce an inflammatory response, as can activation of S1P receptor 2. Omega-3 fatty acids and resolvins have anti-inflammatory or proresolving effects. Increase in cAMP or activation of the G protein-coupled receptor, ChemR23, may drive macrophages toward a resolving phenotype, Mres.