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

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)alpha in primary monocytes and macrophages. LXR agonists promote RAR alpha gene transcription through binding to a specific LXR response element on RAR alpha gene promoter. Preincubation of monocytes or macrophages with LXR agonists before RAR alpha agonist treatment enhances synergistically the expression of several RAR alpha target genes. One of these genes encodes transglutaminase (TGM) 2, a key factor required for macrophage phagocytosis. Accordingly, the combination of LXR and RAR alpha 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 alpha-TGM2-dependent mechanism. A combination of LXR/RAR alpha 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. (Circ Res. 2009; 105: 393-401.)