Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages

Si Yoon Kim, Eun Jin Lim, Young So Yoon, Young Ho Ahn, Eun Mi Park, Hee Sun Kim, Jihee Lee Kang

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Mer signaling increases the transcriptional activity of liver X receptor (LXR) to promote the resolution of acute sterile inflammation. Here, we aimed to understand the pathway downstream of Mer signaling after growth arrest-specific protein 6 (Gas6) treatment that leads to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). Gas6-induced increases in LXRα and LXRβ and expression of their target genes were inhibited in BMDM from STAT1 -/- mice or by the STAT1-specific inhibitor fludarabine. Gas6-induced STAT1 phosphorylation, LXR activation, and LXR target gene expression were inhibited in BMDM from Mer -/- mice or by inhibition of PI3K or Akt. Gas6-induced Akt phosphorylation was inhibited in BMDM from STAT1 -/- mice or in the presence of fludarabine. Gas6-induced LXR activity was enhanced through an interaction between LXRα and STAT1 on the DNA promoter of Arg2. Additionally, we found that Gas6 inhibited lipopolysaccharide (LPS)-induced nitrite production in a STAT1 and LXR pathway-dependent manner in BMDM. Additionally, Mer-neutralizing antibody reduced LXR and Arg2 expression in lung tissue and enhanced NO production in bronchoalveolar lavage fluid in LPS-induced acute lung injury. Our data suggest the possibility that the Gas6-Mer-PI3K/Akt-STAT1-LXR-Arg2 pathway plays an essential role for resolving inflammatory response in acute lung injury.

Original languageEnglish
Article number29673
JournalScientific Reports
Volume6
DOIs
StatePublished - 13 Jul 2016

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