Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-δ and UCP2

Éva Garabuczi, Zsolt Sarang, Zsuzsa Szondy

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S- and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis-related genes MERTK, C1q, UCP2, and the transcription factor C/EBPβ. C/EBPβ contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPARδ, RARα, RXRα and RALDH1, the latter one in an LXR- and RARα-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPARδ upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases.

Original languageEnglish
Pages (from-to)573-582
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1853
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

Peroxisome Proliferator-Activated Receptors
Glucocorticoids
Retinoids
Macrophages
Lipids
Phagocytosis
Liver X Receptors
Retinaldehyde
Cytophagocytosis
Protein S
Autoimmunity
Genes
Oxidoreductases
Chronic Disease
Transcription Factors
Up-Regulation
Inflammation

Keywords

  • Efferocytosis
  • Glucocorticoid
  • LXR
  • Macrophage
  • PPARδ
  • UCP2

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

@article{6e7f44904b2c4d9297862fa9143d0376,
title = "Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-δ and UCP2",
abstract = "Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S- and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis-related genes MERTK, C1q, UCP2, and the transcription factor C/EBPβ. C/EBPβ contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPARδ, RARα, RXRα and RALDH1, the latter one in an LXR- and RARα-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPARδ upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases.",
keywords = "Efferocytosis, Glucocorticoid, LXR, Macrophage, PPARδ, UCP2",
author = "{\'E}va Garabuczi and Zsolt Sarang and Zsuzsa Szondy",
year = "2015",
month = "3",
day = "1",
doi = "10.1016/j.bbamcr.2014.12.014",
language = "English",
volume = "1853",
pages = "573--582",
journal = "Biochimica et Biophysica Acta - Molecular Cell Research",
issn = "0167-4889",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-δ and UCP2

AU - Garabuczi, Éva

AU - Sarang, Zsolt

AU - Szondy, Zsuzsa

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S- and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis-related genes MERTK, C1q, UCP2, and the transcription factor C/EBPβ. C/EBPβ contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPARδ, RARα, RXRα and RALDH1, the latter one in an LXR- and RARα-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPARδ upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases.

AB - Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S- and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis-related genes MERTK, C1q, UCP2, and the transcription factor C/EBPβ. C/EBPβ contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPARδ, RARα, RXRα and RALDH1, the latter one in an LXR- and RARα-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPARδ upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases.

KW - Efferocytosis

KW - Glucocorticoid

KW - LXR

KW - Macrophage

KW - PPARδ

KW - UCP2

UR - http://www.scopus.com/inward/record.url?scp=84920147417&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920147417&partnerID=8YFLogxK

U2 - 10.1016/j.bbamcr.2014.12.014

DO - 10.1016/j.bbamcr.2014.12.014

M3 - Article

C2 - 25523142

AN - SCOPUS:84920147417

VL - 1853

SP - 573

EP - 582

JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

SN - 0167-4889

IS - 3

ER -