Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor alpha pathway increases the clearance of apoptotic cells by human macrophages.

نویسندگان

  • 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
چکیده

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 RARalpha gene transcription through binding to a specific LXR response element on RARalpha gene promoter. Preincubation of monocytes or macrophages with LXR agonists before RARalpha agonist treatment enhances synergistically the expression of several RARalpha target genes. One of these genes encodes transglutaminase (TGM)2, a key factor required for macrophage phagocytosis. Accordingly, the combination of LXR and RARalpha 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 RARalpha-TGM2-dependent mechanism. A combination of LXR/RARalpha 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.

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

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عنوان ژورنال:
  • Circulation research

دوره 105 4  شماره 

صفحات  -

تاریخ انتشار 2009