Journal article
Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation
The Journal of immunology (1950), Vol.194(7), pp.3295-3304
04/01/2015
DOI: 10.4049/jimmunol.1402691
PMCID: PMC4369436
PMID: 25710911
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.
Details
- Title: Subtitle
- Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation
- Creators
- Amol Suryawanshi - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912Indumathi Manoharan - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912Yuan Hong - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912Daniel Swafford - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912Tanmay Majumdar - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA 30912M Mark Taketo - Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, JapanBalaji Manicassamy - Department of Microbiology, University of Chicago, Chicago, IL 60637Pandelakis A Koni - 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 30912Muthusamy Thangaraju - Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912Zuoming Sun - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; andAndrew L Mellor - 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 30912David H Munn - 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 30912Santhakumar Manicassamy - 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
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.194(7), pp.3295-3304
- DOI
- 10.4049/jimmunol.1402691
- PMID
- 25710911
- PMCID
- PMC4369436
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 CA103320 / NCI NIH HHS R01 DK097271 / NIDDK NIH HHS R01 AI109644 / NIAID NIH HHS DK097271 / NIDDK NIH HHS R56 AI104875 / NIAID NIH HHS UL1 TR000430 / NCATS NIH HHS AI04875 / NIAID NIH HHS R01 CA096651 / NCI NIH HHS
- Language
- English
- Date published
- 04/01/2015
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083876502771
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