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(Circulation Research. 2009;105:393.)
© 2009 American Heart Association, Inc.

Clinical Research

Induction of Transglutaminase 2 by a Liver X Receptor/Retinoic Acid Receptor Pathway Increases the Clearance of Apoptotic Cells by Human Macrophages

Cédric Rébé, Magalie Raveneau, Angélique Chevriaux, Daniela Lakomy, Anne-Laure Sberna, Annie Costa, Ginette Bessède, Anne Athias, Eric Steinmetz, Jean Marc A. Lobaccaro, Georges Alves, Alexandre Menicacci, Sébastien Vachenc, Eric Solary, Philippe Gambert, David Masson

From the Institut Fédératif de Recherche Santé-STIC (C.R., M.R., A.C., D.L., A.-L.S., A.C., G.B., A.A., E.S., P.G., D.M.) and Centre de Recherche-UMR866 (D.L., A.-L.S., E.S., E.S., P.G., D.M.), Faculté de Médecine, Université de Bourgogne, Dijon; Centre National de la Recherche Scientifique UMR6247-GReD and Centre de Recherche en Nutrition Humaine (J.M.A.L., G.A.) Clermont Université 24, Aubière; and Solvay Pharmaceuticals (A.M., S.V.), Bioinformatics Team, Exploratory Biological Unit, Daix, France. Present address for C.R.: Centre de Recherche-UMR866, Equipe "Avenir," Anti-cancer Centre Georges-François LECLERC, 21000 Dijon, France.

Correspondence to Cédric Rebe, INSERM U866, 7 bd Jeanne d'Arc, 21079 Dijon cedex, France. E-mail cedricrebe{at}yahoo.fr or David Masson David.Masson@chu-dijon.fr

Rationale: Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are involved in the control of cholesterol homeostasis and inflammatory response. Human monocytes and macrophages express high levels of these receptors and are appropriate cells to study the response to LXR agonists.

Objective: The purpose of this study was to identify new LXR targets in human primary monocytes and macrophages and the consequences of their activation.

Methods and Results: We show that LXR agonists significantly increase the mRNA and protein levels of the retinoic acid receptor (RAR) in primary monocytes and macrophages. LXR agonists promote RAR gene transcription through binding to a specific LXR response element on RAR gene promoter. Preincubation of monocytes or macrophages with LXR agonists before RAR agonist treatment enhances synergistically the expression of several RAR target genes. One of these genes encodes transglutaminase (TGM)2, a key factor required for macrophage phagocytosis. Accordingly, the combination of LXR and RAR agonists at concentrations found in human atherosclerotic plaques markedly enhances the capabilities of macrophages to engulf apoptotic cells in a TGM2-dependent manner.

Conclusions: These results indicate an important role for LXRs in the control of phagocytosis through an RAR-TGM2–dependent mechanism. A combination of LXR/RAR agonists that may operate in atherosclerosis could also constitute a promising strategy to improve the clearance of apoptotic cells by macrophages in other pathological situations.

Key Words: LXR • RAR • macrophages • phagocytosis • transglutaminase