PMID- 25210120 OWN - NLM STAT- MEDLINE DCOM- 20150107 LR - 20211021 IS - 1550-6606 (Electronic) IS - 0022-1767 (Print) IS - 0022-1767 (Linking) VI - 193 IP - 8 DP - 2014 Oct 15 TI - TLR2-dependent activation of beta-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. PG - 4203-13 LID - 10.4049/jimmunol.1400614 [doi] AB - 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 beta-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of beta-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 beta-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the beta-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of beta-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation. CI - Copyright (c) 2014 by The American Association of Immunologists, Inc. FAU - Manoharan, Indumathi AU - Manoharan I AD - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; FAU - Hong, Yuan AU - Hong Y AD - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; FAU - Suryawanshi, Amol AU - Suryawanshi A AD - Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; FAU - Angus-Hill, Melinda L AU - Angus-Hill ML AD - Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112; FAU - Sun, Zuoming AU - Sun Z AD - Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; FAU - Mellor, Andrew L AU - Mellor AL AD - 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. FAU - Munn, David H AU - Munn DH AD - 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. FAU - Manicassamy, Santhakumar AU - Manicassamy S AD - 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. LA - eng GR - DK097271/DK/NIDDK NIH HHS/United States GR - R01 AI109644/AI/NIAID NIH HHS/United States GR - R01 CA103320/CA/NCI NIH HHS/United States GR - R01 CA096651/CA/NCI NIH HHS/United States GR - R56 AI104875/AI/NIAID NIH HHS/United States GR - AI04875/AI/NIAID NIH HHS/United States GR - R01 DK097271/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140910 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (IL10 protein, mouse) RN - 0 (Lectins, C-Type) RN - 0 (Tcf7l2 protein, mouse) RN - 0 (Tlr2 protein, mouse) RN - 0 (Toll-Like Receptor 2) RN - 0 (Transcription Factor 7-Like 2 Protein) RN - 0 (beta Catenin) RN - 0 (dectin 1) RN - 130068-27-8 (Interleukin-10) RN - 9010-72-4 (Zymosan) RN - EC 1.2.1 (Aldehyde Dehydrogenase 1 Family) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) RN - EC 1.2.1.36 (Aldh1a2 protein, mouse) RN - EC 1.2.1.36 (Retinal Dehydrogenase) RN - EC 2.7.11.1 (Akt1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Adoptive Transfer MH - Aldehyde Dehydrogenase/biosynthesis MH - Aldehyde Dehydrogenase 1 Family MH - Animals MH - Autoimmunity/*immunology MH - Cell Differentiation/immunology MH - Dendritic Cells/*immunology MH - Encephalomyelitis, Autoimmune, Experimental/chemically induced/immunology MH - Inflammation/immunology/prevention & control MH - Interleukin-10/biosynthesis MH - Lectins, C-Type/immunology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Proto-Oncogene Proteins c-akt/immunology MH - Retinal Dehydrogenase MH - T-Lymphocytes, Regulatory/*cytology MH - Th1 Cells/cytology/immunology MH - Th17 Cells/cytology/immunology MH - Toll-Like Receptor 2/*immunology MH - Transcription Factor 7-Like 2 Protein/immunology MH - Zymosan/immunology/pharmacology MH - beta Catenin/genetics/*metabolism PMC - PMC4185231 MID - NIHMS620670 EDAT- 2014/09/12 06:00 MHDA- 2015/01/08 06:00 PMCR- 2015/10/15 CRDT- 2014/09/12 06:00 PHST- 2014/09/12 06:00 [entrez] PHST- 2014/09/12 06:00 [pubmed] PHST- 2015/01/08 06:00 [medline] PHST- 2015/10/15 00:00 [pmc-release] AID - jimmunol.1400614 [pii] AID - 10.4049/jimmunol.1400614 [doi] PST - ppublish SO - J Immunol. 2014 Oct 15;193(8):4203-13. doi: 10.4049/jimmunol.1400614. Epub 2014 Sep 10.