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

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.

Crucial role of Mer tyrosine kinase in the maintenance of SIGN‐R1+ marginal zone macrophages

“…Consistent with the flow cytometry data, SIGN‐R1 and MARCO expression in the splenic MZ was restored to a certain extent in Mer −/− mice treated with GW3965 diet than in Mer −/− mice on a regular diet (Figure e). LXRs are known to promote anti‐inflammatory signaling pathways in immune cells . In accordance, when we challenged Mer −/− macrophages with ACs in the presence of LXR agonist GW3965, we found that the TNFα production by these macrophages was reduced by almost twofold (Figure f).…”

“…Several recent reports have indicated the interdependence of Mer signaling and LXR transcriptional activity in macrophages. The activation of LXRs during AC clearance induces Mer expression, whereas Mer signaling in macrophages increases the anti‐inflammatory transcriptional activity of LXRs . Most importantly, LXRα is the only known transcriptional regulator of macrophage differentiation in the splenic marginal zone, where it is essential for the differentiation of SIGN‐R1 + MZMs and CD169 + MMMs .…”

Inhibition of p38mapk Reduces Adipose Tissue Inflammation in Aging Mediated by Arginase-II

“…This finding has been further supported by studies from other groups [23,24]. However, the anti-inflammatory function of Arg-II in macrophages is also described in the literature [25][26][27]. To our knowledge, the role of Arg-II in age-associated adipose tissue macrophage inflammation and the underlying molecular mechanisms are not clear.…”

“…Interestingly, the enhanced Arg-I levels in the aging adipose tissue under Arg-II deficiency are correlated with decreased age-associated inflammation, that is, macrophage accumulation and IL-6 levels in the adipose tissue, which could be due to the fact that Arg-I is upregulated in the M2-like macrophages which play an anti-inflammatory role [38][39][40][41][42]. In contrast to Arg-I, Arg-II is often associated with pro-inflammatory M1-like phenotype cells [18,41], although controversies are reported in the literature [18,[22][23][24][25][26][27]. The reasons for the controversies are not clear; it is most likely due to the different inflammation disease models.…”

Liver X receptors link lipid metabolism and inflammation

“…Interestingly, overexpression of ABCA1 induces expression of the anti-inflammatory cytokine IL10, a marker of the M2 macrophage phenotype, via a protein kinase A-dependent pathway [98]. Activation of LXRs has also been shown to increase expression of arginase 1 and arginase 2, two additional markers of the M2 phenotype [102][103][104]. These studies support the hypothesis that LXRs function to counterinflammation and favor resolution of the inflammatory response.…”