IMMUNOPATHOLOGY AND INFECTIOUS DISEASES FOXO 1 Deletion Reduces Dendritic Cell Function and Enhances Susceptibility to Periodontitis

The host response plays both protective and destructive roles in periodontitis. FOXO1 is a transcription factor that is activated in dendritic cells (DCs), but its function in vivo has not been examined. We investigated the role of FOXO1 in activating DCs in experimental (CD11c.Cre+.FOXO1L/L) compared with matched control mice (CD11c.Cre−.FOXO1L/L) in response to oral pathogens. Lineage-specific FOXO1 deletion reduced the recruitment of DCs to oral mucosal epithelium by approximately 40%. FOXO1 was needed for expression of genes that regulate migration, including integrins αν and β3 and matrix metalloproteinase-2. Ablation of FOXO1 in DCs significantly decreased IL-12 produced by DCs in mucosal surfaces. Moreover, FOXO1 deletion reduced migration of DCs to lymph nodes, reduced capacity of DCs to induce formation of plasma cells, and reduced production of bacteria-specific antibody. The decrease in DC function in the experimental mice led to increased susceptibility to periodontitis through a mechanism that involved a compensatory increase in osteoclastogenic factors, IL-1β, IL-17, and RANKL. Thus, we reveal a critical role for FOXO1 in DC recruitment to oral mucosal epithelium and activation of adaptive immunity induced by oral inoculation of bacteria. Disciplines Dentistry Author(s) Wenmei Xiao, Guangyu Dong, Sandra Pacios, Maher Alnammary, Laura A. Barger, Yu Wang, Yingying Wu, and Dana T. Graves This journal article is available at ScholarlyCommons: https://repository.upenn.edu/dental_papers/62 IMMUNOPATHOLOGY AND INFECTIOUS DISEASES FOXO1 Deletion Reduces Dendritic Cell Function and Enhances Susceptibility to Periodontitis Wenmei Xiao,*y Guangyu Dong,y Sandra Pacios,y Maher Alnammary,y Laura A. Barger,y Yu Wang,yz Yingying Wu,y and Dana T. Gravesy From the Department of Periodontology,* School and Hospital of Stomatology, Peking University, Beijing, China; the Department of Periodontics,y School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Implantology,z School of Stomatology, Jilin University,

[1]  D. Graves,et al.  FOXO Transcription Factors: Their Clinical Significance and Regulation , 2014, BioMed research international.

[2]  S. Holland,et al.  Defective Neutrophil Recruitment in Leukocyte Adhesion Deficiency Type I Disease Causes Local IL-17–Driven Inflammatory Bone Loss , 2014, Science Translational Medicine.

[3]  A. Kantarcı,et al.  Inflammatory and immune pathways in the pathogenesis of periodontal disease. , 2014, Periodontology 2000.

[4]  D. Graves,et al.  P. gingivalis Modulates Keratinocytes through FOXO Transcription Factors , 2013, PloS one.

[5]  L. Xing,et al.  Osteoclast fusion and regulation by RANKL-dependent and independent factors. , 2012, World journal of orthopedics.

[6]  A. Bolstad,et al.  Gingival lymphatic drainage protects against Porphyromonas gingivalis-induced bone loss in mice. , 2012, The American journal of pathology.

[7]  L. Shapira,et al.  Langerhans cells down-regulate inflammation-driven alveolar bone loss , 2012, Proceedings of the National Academy of Sciences.

[8]  C. Zenobia,et al.  The relationship of the oral microbiotia to periodontal health and disease. , 2011, Cell host & microbe.

[9]  R. Förster,et al.  CCR7 Essentially Contributes to the Homing of Plasmacytoid Dendritic Cells to Lymph Nodes under Steady-State As Well As Inflammatory Conditions , 2011, The Journal of Immunology.

[10]  D. Graves,et al.  Inflammation and Uncoupling as Mechanisms of Periodontal Bone Loss , 2011, Journal of dental research.

[11]  R. Pacifici.  The immune system and bone. , 2010, Archives of biochemistry and biophysics.

[12]  E. Gravallese,et al.  Bone damage in rheumatoid arthritis: mechanistic insights and approaches to prevention. , 2010, Rheumatic diseases clinics of North America.

[13]  C. Cutler,et al.  Targeting of DC-SIGN on Human Dendritic Cells by Minor Fimbriated Porphyromonas gingivalis Strains Elicits a Distinct Effector T Cell Response1 , 2009, The Journal of Immunology.

[14]  N. Yamada,et al.  The Involvement of IL-23 and the Th17 Pathway in Periodontitis , 2009, Journal of dental research.

[15]  E. Weiss,et al.  Mouse model of experimental periodontitis induced by Porphyromonas gingivalis/Fusobacterium nucleatum infection: bone loss and host response. , 2009, Journal of clinical periodontology.

[16]  Daniel R. Beisner,et al.  Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor , 2009, Nature Immunology.

[17]  D. Graves,et al.  Activation of the Acquired Immune Response Reduces Coupled Bone Formation in Response to a Periodontal Pathogen1 , 2008, The Journal of Immunology.

[18]  D. Graves.  Cytokines that promote periodontal tissue destruction. , 2008, Journal of periodontology.

[19]  T. Uematsu,et al.  Inorganic Polyphosphate: a Possible Stimulant of Bone Formation , 2007, Journal of dental research.

[20]  J. Penninger,et al.  Dendritic Cells at the Osteo‐Immune Interface: Implications for Inflammation‐Induced Bone Loss , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  Y. Konttinen,et al.  MMPs, IL-1, and TNF are Regulated by IL-17 in Periodontitis , 2007, Journal of dental research.

[22]  J. A. Aas,et al.  The breadth of bacterial diversity in the human periodontal pocket and other oral sites. , 2006, Periodontology 2000.

[23]  U. Lerner.  Inflammation-induced Bone Remodeling in Periodontal Disease and the Influence of Post-menopausal Osteoporosis , 2006, Journal of dental research.

[24]  D. Graves,et al.  Diabetes Enhances Periodontal Bone Loss through Enhanced Resorption and Diminished Bone Formation , 2006, Journal of dental research.

[25]  C. Leclerc,et al.  Purification of splenic dendritic cells induces maturation and capacity to stimulate Th1 response in vivo. , 2006, International immunology.

[26]  X. Dereka,et al.  Factor XIIIa+ dendritic cells and S-100 protein+ Langerhans' cells in adult periodontitis. , 2004, Journal of periodontal research.

[27]  F. C. Gibson,et al.  Mice Lacking Monocyte Chemoattractant Protein 1 Have Enhanced Susceptibility to an Interstitial Polymicrobial Infection Due to Impaired Monocyte Recruitment , 2002, Infection and Immunity.

[28]  J. Penninger,et al.  Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection. , 2000, The Journal of clinical investigation.

[29]  Sundeep Khosla,et al.  The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone Resorption , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  D. Kinane,et al.  Innate cellular responses to the periodontal biofilm. , 2012, Frontiers of oral biology.

[31]  G. Garlet.  Critical Reviews in Oral Biology & Medicine: Destructive and Protective Roles of Cytokines in Periodontitis: A Re-appraisal from Host Defense and Tissue Destruction Viewpoints , 2010 .

[32]  J. Roes,et al.  Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. von Bubnoff,et al.  Skin homing of Langerhans cell precursors: adhesion, chemotaxis, and migration. , 2006, The Journal of allergy and clinical immunology.

[34]  G. Taylor,et al.  Prevalence and trends in periodontitis in the USA: the [corrected] NHANES, 1988 to 2000. , 2005, Journal of dental research.

[35]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.