title: Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation.
abstract: Breakdown in immunological tolerance to self-Ags or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. In this study, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (lipoprotein receptor-related protein [LRP]5/6) or downstream (β-catenin) mediators of canonical wnt signaling in mice exacerbated experimental autoimmune encephalomyelitis pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/Th17 cell differentiation but reduced regulatory T cell response. This was due to increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed experimental autoimmune encephalomyelitis onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Indumathi
authors.initials: I
authors.lastname: Manoharan
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Daniel
authors.initials: D
authors.lastname: Swafford
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912;
authors.forename: Tanmay
authors.initials: T
authors.lastname: Majumdar
authors.affiliation: Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan;
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL 60637;
authors.forename: Balaji
authors.initials: B
authors.lastname: Manicassamy
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and.
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; smanicassamy@gru.edu.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D016212:Transforming Growth Factor beta; D060509:Wnt3A Protein; D051176:beta Catenin; D016753:Interleukin-10