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,Eun-Mi Park,Jihee Lee Kang,Young-So Yoon,Hee-Sun Kim,Young-Ho Ahn

doi:10.1038/srep29673

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.

Highlights

Liver X receptors (LXR) were originally identified as ligand-dependent transcriptional activators belonging to a nuclear receptor superfamily[1,2]
We previously reported that Gas[6] enhances the abundance of LXRαand LXRβand their target genes, which are involved in cholesterol and lipid metabolism, in RAW 264.7 cells[16]
We confirmed that Mer signaling is involved in Growth arrest-specific protein 6 (Gas6)-induced LXRαand LXRβexpression and activation in mouse bone-marrow derived macrophages (BMDM), as LXRαand LXRβmRNA and protein were reduced in BMDM from Mer−/− mice

Summary

Introduction

Liver X receptors (LXR) were originally identified as ligand-dependent transcriptional activators belonging to a nuclear receptor superfamily[1,2]. LXRs have emerged as important regulators of inflammatory gene expression, innate immunity, and autoimmune diseases[8,9,10,11]. LXR has been demonstrated to up-regulate the expression of genes involved in immune and inflammatory responses, such as apoptotic inhibitor of macrophages (AIM), arginase 2 (Arg2), and vascular endothelial growth factor (VEGF)[11]. We elucidated a previously uncharacterized pathway that involves Mer signaling in peritoneal macrophages, spleen, and lung that leads to a progressive increase in LXR mRNA and protein abundance and activation over the course of acute inflammation. We aimed to understand the pathways downstream of Gas6/Mer signaling that lead to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). We provide in vivo evidence using Mer-neutralizing antibody that Gas6/Mer signaling modulates NO production through activation of LXR/Arg[2] pathway in LPS-induced acute lung injury, which in part promotes the resolution of acute lung injury[17]

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