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Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.

ABSTRACT: Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophages exhibited a selective defect in phagocytosis of apoptotic cells and an aberrant proinflammatory response to them. As a consequence of these defects, mice lacking LXRs manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorated disease progression in a mouse model of lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.

SUBMITTER: A-Gonzalez N

PROVIDER: S-EPMC2791787 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.

A-Gonzalez Noelia N Bensinger Steven J SJ Hong Cynthia C Beceiro Susana S Bradley Michelle N MN Zelcer Noam N Deniz Jose J Ramirez Cristina C Díaz Mercedes M Gallardo German G de Galarreta Carlos Ruiz CR Salazar Jon J Lopez Felix F Edwards Peter P Parks John J Andujar Miguel M Tontonoz Peter P Castrillo Antonio A

Immunity 20090730 2

Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophage ...[more]

PMID: 19646905

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Project description:The farnesoid X receptor (FXR) is known to regulate the gene expression of SR‑BI, which mediates plasma high‑density lipoprotein (HDL)‑cholesterol uptake. Our previous study demonstrated that the activation of FXR by obeticholic acid (OCA) lowered plasma HDL‑cholesterol levels and increased the hepatic mRNA and protein expression levels of SR‑BI in hypercholesterolemic hamsters, but not in normolipidemic hamsters, suggesting that dietary cholesterol may be involved in the OCA‑induced transcription of SR‑BI. In the present study, a functional 90‑base‑pair regulatory region was identified in the first intron of the SR‑BI gene of hamster and mouse that contains a FXR response element (IR‑1) and an adjacent liver X receptor (LXR) response element (LXRE). By in vitro DNA binding and luciferase reporter gene assays, it was demonstrated that FXR and LXR bind to their recognition sequences within this intronic region and transactivate the SR‑BI reporter gene in a synergistic manner. It was also shown that mutations at either the IR‑1 site or the LXRE site eliminated OCA‑mediated gene transcription. Utilizing chow‑fed hamsters as an in vivo model, it was demonstrated that treating normolipidemic hamsters with OCA or GW3965 alone did not effectively induce levels of SR‑BI, whereas their combined treatment significantly increased the mRNA and protein levels of SR‑BI in the liver. The study further investigated effects of FXR and LXR coactivation on the gene expression of SR‑BI in human liver cells. The intronic FXRE and LXRE regulatory region was not conserved in the human SR‑BI genomic sequence, however, higher mRNA expression levels of SR‑BI were observed in human primary hepatocytes and HepG2 cells exposed to combined treatments of FXR and LXR agonists, compared with those in cells exposed to individual ligand treatment. Therefore, these results suggest that human SR‑BI gene transcription may also be subject to concerted activation by FXR and LXR, mediated via currently unidentified regulatory sequences.

Dataset Information

Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.

Publications

Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.

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