Journal Article

Deficiency of Nuclear Receptor Nur77 Aggravates Mouse Experimental Colitis by Increased NFκB Activity in Macrophages

van Tiel, Claudia M., Meijer, Sybren L., Huveneers, Stephan, Vos, Mariska, de Jonge, Wouter J., de Vries, Carlie J. M., Marinković, Goran, van Stalborch, Anne-Marieke, Hamers, Anouk A. J., van Dam, Laura, Teixeira Duarte, José M., te Velde, Anje A.

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Animal models / Animals / Biochemistry / Bone marrow / Cell Line / Colitis - chemically induced / Colitis - immunology / Colitis - metabolism / Colitis, Ulcerative - metabolism / Colitis, Ulcerative - pathology / Colon / Colon - metabolism / Colon - pathology / Crohn Disease - metabolism / Crohn Disease - pathology / Crohn's disease / Cytokines / Cytokines - biosynthesis / Cytokines - genetics / Dendritic cells / Dextran / Dextran Sulfate - toxicity / Disease Models, Animal / Epithelial cells / Epithelial Cells - metabolism / Epithelial Cells - pathology / Epithelium / Female / Forkhead Transcription Factors - biosynthesis / Forkhead Transcription Factors - genetics / Foxp3 protein / Gastroenterology / Gene expression / Gene Expression Regulation / Humans / Immunity / Immunology / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory diseases / Interleukin 10 / Interleukin 6 / Interleukin 8 / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestine / Life sciences / Lipopolysaccharides / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - metabolism / Medical treatment / Mice / Mice, Inbred C57BL / Mice, Knockout / Monocyte chemoattractant protein 1 / Monocytes / NF-kappa B - metabolism / NF-κB protein / Nuclear Receptor Subfamily 4, Group A, Member 1 - deficiency / Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics / Nuclear Receptor Subfamily 4, Group A, Member 1 - immunology / Nur77 protein / Permeability / Proteins / RAW 264.7 Cells / Ribonucleic acid / RNA / Rodents / Sodium / Sodium sulfate / Sulfonic acid / Trinitrobenzenesulfonic Acid - toxicity / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Ulcerative colitis