title: FOXO1 regulates dendritic cell activity through ICAM-1 and CCR7.
abstract: The transcription factor FOXO1 regulates cell function and is expressed in dendritic cells (DCs). We investigated the role of FOXO1 in activating DCs to stimulate a lymphocyte response to bacteria. We show that bacteria induce FOXO1 nuclear localization through the MAPK pathway and demonstrate that FOXO1 is needed for DC activation of lymphocytes in vivo. This occurs through FOXO1 regulation of DC phagocytosis, chemotaxis, and DC-lymphocyte binding. FOXO1 induces DC activity by regulating ICAM-1 and CCR7. FOXO1 binds to the CCR7 and ICAM-1 promoters, stimulates CCR7 and ICAM-1 transcriptional activity, and regulates their expression. This is functionally important because transfection of DCs from FOXO1-deleted CD11c.Cre(+)FOXO1(L/L) mice with an ICAM-1-expressing plasmid rescues the negative effect of FOXO1 deletion on DC bacterial phagocytosis and chemotaxis. Rescue with both CCR7 and ICAM-1 reverses impaired DC homing to lymph nodes in vivo when FOXO1 is deleted. Moreover, Ab production following injection of bacteria is significantly reduced with lineage-specific FOXO1 ablation. Thus, FOXO1 coordinates upregulation of DC activity through key downstream target genes that are needed for DCs to stimulate T and B lymphocytes and generate an Ab defense to bacteria.
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Guangyu
authors: G
authors: Dong
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China;
authors: Yu
authors: Y
authors: Wang
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Periodontology, School and Hospital of Stomatology, Peking University, Beijing 100081, China;
authors: Wenmei
authors: W
authors: Xiao
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Sandra
authors: S
authors: Pacios Pujado
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China;
authors: Fanxing
authors: F
authors: Xu
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors: Chen
authors: C
authors: Tian
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing 100081, China; and.
authors: E
authors: E
authors: Xiao
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Yongwon
authors: Y
authors: Choi
authors: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; dtgraves@dental.upenn.edu.
authors: Dana T
authors: DT
authors: Graves
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology*
chemical_list: C515371:Ccr7 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C090509:Icam1 protein, mouse; D054400:Receptors, CCR7; D018799:Intercellular Adhesion Molecule-1