title: Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity.
abstract: Chronic inflammation contributes to numerous diseases, and regulation of inflammation is crucial for disease control and resolution. Sex hormones have potent immunoregulatory abilities. Specifically, estrogen influences immune cells and inflammation, which contributes to the sexual dimorphism of autoimmunity and protection against disease seen during pregnancy in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although long thought to act primarily on T cells, recent evidence demonstrated that myeloid cells, such as dendritic cells (DCs), are essential in mediating estrogen's protective effects. Estriol (E3), a pregnancy-specific estrogen, has therapeutic efficacy in MS and EAE, and we evaluated whether E3 could act exclusively through DCs to protect against the inflammatory autoimmune disease EAE. Levels of activation markers (CD80 and CD86) and inhibitory costimulatory markers (PD-L1, PD-L2, B7-H3, and B7-H4) were increased in E3 DCs. E3 DCs had decreased proinflammatory IL-12, IL-23, and IL-6 mRNA expression, increased immunoregulatory IL-10 and TGF-β mRNA expression, and a decreased ratio of IL-12/IL-10 protein production. Importantly, transfer of E3 DCs to mice prior to active induction of EAE protected them from developing EAE through immune deviation to a Th2 response. This protection was apparent, even in the face of in vitro and in vivo inflammatory challenge. In summary, our results showed that E3 generates tolerogenic DCs, which protect against the inflammatory autoimmune disease EAE. Targeted generation of tolerogenic DCs with immunomodulatory therapeutics, such as E3, has potential applications in the treatment of numerous autoimmune and chronic inflammatory diseases.
authors.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA. papenfuss.1@osu.edu
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Papenfuss
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Powell
authors.forename: Melanie A
authors.initials: MA
authors.lastname: McClain
authors.forename: Ashley
authors.initials: A
authors.lastname: Bedarf
authors.forename: Amber
authors.initials: A
authors.lastname: Singh
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Gienapp
authors.forename: Todd
authors.initials: T
authors.lastname: Shawler
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Whitacre
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004964:Estriol / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006131:Growth Inhibitors / Q000502:physiology; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation
chemical_list: D015415:Biomarkers; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D011257:Pregnancy Proteins; D004964:Estriol