Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: A crucial role for Krüppel-like factor 2

• Published in: Atherosclerosis Vol. 214; no. 2; pp. 345 - 349
• Main Authors: van Tits, L.J.H, Stienstra, R, van Lent, P.L, Netea, M.G, Joosten, L.A.B, Stalenhoef, A.F.H
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01-02-2011; Elsevier
• Subjects: atherogenesis; atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Cells, Cultured; Chemokine CCL2 - metabolism; Coronary heart disease; Cytokines; Cytokines - metabolism; endothelial cells; foam cells; Foam Cells - drug effects; Foam Cells - immunology; Foam Cells - metabolism; foaming; Gene expression; gene expression regulation; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Heart; Humans; inflammation; Inflammation Mediators - metabolism; interleukin-10; Interleukin-10 - metabolism; interleukin-6; Interleukin-6 - metabolism; interleukin-8; Interleukin-8 - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Krüppel-like factor 2; Lipopolysaccharides - pharmacology; Lipoproteins, LDL - metabolism; low density lipoprotein; Macrophage Activation - drug effects; Macrophage Colony-Stimulating Factor - metabolism; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages differentiation; Medical sciences; monocytes; Oxidized LDL accumulation; pathogenesis; Phenotype; RNA Interference; secretion; small interfering RNA; Time Factors; transcription factors; Transfection; Macrophages differentiation; Cytokines; Gene expression; Krüppel-like factor 2; Oxidized LDL accumulation; Vascular disease; Lipoprotein LDL; Atherosclerosis; Cytokine; Cardiovascular disease; Macrophage
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2010.11.018

Abstract Objective Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. Methods and results Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Krüppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Krüppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Krüppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion. Conclusions We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Krüppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.