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


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.
Rébé
Cédric
C
Institut Fédératif de Recherche Santé-STIC, Faculté de Médecine, Université de Bourgogne, Dijon, France. cedricrebe@yahoo.fr
Raveneau
Magalie
M
Chevriaux
Angélique
A
Lakomy
Daniela
D
Sberna
Anne-Laure
AL
Costa
Annie
A
Bessède
Ginette
G
Athias
Anne
A
Steinmetz
Eric
E
Lobaccaro
Jean Marc A
JM
Alves
Georges
G
Menicacci
Alexandre
A
Vachenc
Sébastien
S
Solary
Eric
E
Gambert
Philippe
P
Masson
David
D
D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D004790:Enzyme Induction; D019204:GTP-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D000071518:Liver X Receptors; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology*; D057093:Orphan Nuclear Receptors; D010587:Phagocytosis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D011503:Transglutaminases / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C000717608:TGM2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins