title: Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis.
abstract: The orphan nuclear receptor Nr4a2 is known to modulate both inflammatory and metabolic processes, but the mechanism by which it regulates innate inflammatory homeostasis has not been adequately addressed. This study shows that exposure to ligands for Toll-like receptors (TLRs) robustly induces Nr4a2 and that this induction is tightly regulated by the PI3K-Akt signaling axis. Interestingly, exogenous expression of Nr4a2 in macrophages leads to their alternative phenotype with induction of genes that are prototypical M2 markers. Moreover, Nr4a2 transcriptionally activates arginase 1 expression by directly binding to its promoter. Adoptive transfer experiments revealed that increased survival of animals in endotoxin-induced sepsis is Nr4a2-dependent. Thus our data identify a previously unknown role for Nr4a2 in the regulation of macrophage polarization.
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Sahil
authors.initials: S
authors.lastname: Mahajan
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Saini
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Vemika
authors.initials: V
authors.lastname: Chandra
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Nanduri
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Rashi
authors.initials: R
authors.lastname: Kalra
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Ella
authors.initials: E
authors.lastname: Bhagyaraj
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Khatri
authors.affiliation: From the Institute of Microbial Technology, Council of Scientific and Industrial Research, Chandigarh 160036, India pawan@imtech.res.in.
authors.forename: Pawan
authors.initials: P
authors.lastname: Gupta
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D008024:Ligands; D008070:Lipopolysaccharides; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Arginase 1; M2 macrophages; Nr4a2; gene transcription; inflammation; macrophage; nuclear receptor; sepsis