title: Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages.
abstract: Nuclear receptor Nur77, also referred to as NR4A1 or TR3, plays an important role in innate and adaptive immunity. Nur77 is crucial in regulating the T helper 1/regulatory T-cell balance, is expressed in macrophages and drives M2 macrophage polarization. In this study we aimed to define the function of Nur77 in inflammatory bowel disease. In wild-type and Nur77-/- mice, colitis development was studied in dextran sodium sulphate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced models. To understand the underlying mechanism, Nur77 was overexpressed in macrophages and gut epithelial cells. Nur77 protein is expressed in colon tissues from Crohn's disease and Ulcerative colitis patients and colons from colitic mice in inflammatory cells and epithelium. In both mouse colitis models inflammation was increased in Nur77-/- mice. A higher neutrophil influx and enhanced IL-6, MCP-1 and KC production was observed in Nur77-deficient colons after DSS-treatment. TNBS-induced influx of T-cells and inflammatory monocytes into the colon was higher in Nur77-/- mice, along with increased expression of MCP-1, TNFα and IL-6, and decreased Foxp3 RNA expression, compared to wild-type mice. Overexpression of Nur77 in lipopolysaccharide activated RAW macrophages resulted in up-regulated IL-10 and downregulated TNFα, MIF-1 and MCP-1 mRNA expression through NFκB repression. Nur77 also strongly decreased expression of MCP-1, CXCL1, IL-8, MIP-1α and TNFα in gut epithelial Caco-2 cells. Nur77 overexpression suppresses the inflammatory status of both macrophages and gut epithelial cells and together with the in vivo mouse data this supports that Nur77 has a protective function in experimental colitis. These findings may have implications for development of novel targeted treatment strategies regarding inflammatory bowel disease and other inflammatory diseases.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: van Dam
authors.affiliation: Tytgat Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: José M
authors.initials: JM
authors.lastname: Teixeira Duarte
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mariska
authors.initials: M
authors.lastname: Vos
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Goran
authors.initials: G
authors.lastname: Marinković
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sybren L
authors.initials: SL
authors.lastname: Meijer
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anne-Marieke
authors.initials: AM
authors.lastname: van Stalborch
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Stephan
authors.initials: S
authors.lastname: Huveneers
authors.affiliation: Tytgat Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anje A
authors.initials: AA
authors.lastname: Te Velde
authors.affiliation: Tytgat Institute, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000067996:RAW 264.7 Cells; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate