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Phenotypic modulation of macrophages in response to plaque lipids

Adamson, Samantha; Leitinger, Norbert

doi: 10.1097/MOL.0b013e32834a97e4
Atherosclerosis: cell biology and lipoproteins: Edited by Petri T. Kovanen and Andrew Newby

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.

Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA

Correspondence to Norbert Leitinger, Department of Pharmacology, University of Virginia, 1340 Jefferson Park Avenue, Jordan Hall, 5th Floor, Room 5036/5039, P.O. Box 800735, Charlottesville, VA 22908, USATel: + 1 434 243 6363; fax: + 1 434 924 0149; e-mail:

© 2011 Lippincott Williams & Wilkins, Inc.