title: TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation.
abstract: Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, 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, Medical College of Georgia, 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, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112;
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Angus-Hill
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010;
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, 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, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and smanicassamy@gru.edu.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
mesh_terms: D019264:Adoptive Transfer; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D016753:Interleukin-10 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D050697:Retinal Dehydrogenase; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D058118:Transcription Factor 7-Like 2 Protein / Q000276:immunology; D015054:Zymosan / Q000276:immunology / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D016753:Interleukin-10; D037181:Lectins, C-Type; D051057:Proto-Oncogene Proteins c-akt; D050697:Retinal Dehydrogenase; D051195:Toll-Like Receptor 2; D058118:Transcription Factor 7-Like 2 Protein; D015054:Zymosan; D051176:beta Catenin; D000099181:Dectin-1; C556062:IL10 protein, mouse; C544895:Tcf7l2 protein, mouse; C493486:Tlr2 protein, mouse; C512722:Aldh1a2 protein, mouse; C514862:Akt1 protein, mouse