title: The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis.
abstract: Aryl hydrocarbon receptor (Ahr), a transcription factor, plays a critical role in autoimmune inflammation of the intestine. In addition, microRNAs (miRNAs), small non-coding oligonucleotides, mediate pathogenesis of inflammatory bowel diseases (IBD). However, the precise mechanism and interactions of these molecules in IBD pathogenesis have not yet been investigated. We analyzed the role of Ahr and Ahr-regulated miRNAs in colonic inflammation. Our results show that deficiency of Ahr in intestinal epithelial cells in mice exacerbated inflammation in dextran sodium sulfate-induced colitis. Deletion of Ahr in T cells attenuated colitis, which was manifested by suppressed Th17 cell infiltration into the lamina propria. Candidate miRNA analysis showed that induction of colitis elevated expression of the miR-212/132 cluster in the colon of wild-type mice, whereas in Ahr (-/-) mice, expression was clearly lower. Furthermore, miR-212/132(-/-) mice were highly resistant to colitis and had reduced levels of Th17 cells and elevated levels of IL-10-producing CD4(+) cells. In vitro analyses revealed that induction of type 1 regulatory T (Tr1) cells was significantly elevated in miR-212/132(-/-) T cells with increased c-Maf expression. Our findings emphasize the vital role of Ahr in intestinal homeostasis and suggest that inhibition of miR-212/132 represents a viable therapeutic strategy for treating colitis.
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Ichino
authors: I
authors: Chinen
authors: Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Taisuke
authors: T
authors: Nakahama
authors: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Akihiro
authors: A
authors: Kimura
authors: National Key Laboratory of Gene Technology, Vietnam Academy of Science and Technology (VAST), Institute of Biotechnology, 18 Hoang Quoc Viet Road, Cau Giay, Ha Noi, Vietnam.
authors: Nam T
authors: NT
authors: Nguyen
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Asagi, Saito, Ibaraki-City, Osaka 567-0085, Japan.
authors: Hiroshi
authors: H
authors: Takemori
authors: Laboratory for Immune Signal, National Institute of Biomedical Innovation (NIBIO), 7-6-8 Asagi, Saito, Ibaraki-City, Osaka 567-0085, Japan.
authors: Ayako
authors: A
authors: Kumagai
authors: Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Hisako
authors: H
authors: Kayama
authors: Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Kiyoshi
authors: K
authors: Takeda
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Soyoung
authors: S
authors: Lee
authors: Biological Sciences Department, King Faisal University, PO Box 380, Ahsaa 31982, Saudi Arabia.
authors: Hamza
authors: H
authors: Hanieh
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Barry
authors: B
authors: Ripley
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: David
authors: D
authors: Millrine
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Praveen K
authors: PK
authors: Dubey
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors: Kishan K
authors: KK
authors: Nyati
authors: Medical Research Institute, Medical Genomics, Tokyo Medical Dental University, Tokyo 101-0062, Japan.
authors: Yoshiaki
authors: Y
authors: Fujii-Kuriyama
authors: Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, 37077 Goettingen, Germany.
authors: Kamal
authors: K
authors: Chowdhury
authors: Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871, Japan kishimoto@ifrec.osaka-u.ac.jp.
authors: Tadamitsu
authors: T
authors: Kishimoto
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016264:Dextran Sulfate; D016753:Interleukin-10; D035683:MicroRNAs; D051257:Proto-Oncogene Proteins c-maf; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C556062:IL10 protein, mouse; C546976:MIRN132 microRNA, mouse; C554518:MIRN212 microRNA, mouse; C495608:Maf protein, mouse
keywords: aryl hydrocarbon receptor (Ahr); dextran sodium sulfate (DSS)-induced colitis; inflammatory bowel diseases (IBD); microRNA-212/132 (miR-212/132); type 1 regulatory T (Tr1) cells