title: TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells.
abstract: Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysM(Cre) Tgfbr2(fl/fl) mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS. Tgfbr2 deficiency resulted in increased moDC IL-12 secretion that skewed T cells to produce IFN-γ, which in turn enhanced the production of moDC-derived reactive oxygen species that promote oxidative damage and demyelination. We identified SNPs in the human NOX2 (CYBB) gene that associated with the severity of MS, and significantly increased CYBB expression was recorded in PBMCs from both MS patients and from MS severity risk allele rs72619425-A carrying individuals. We thus identify a novel myeloid cell-T cell activation loop active in the CNS during chronic disease that could be therapeutically targeted. GLIA 2016;64:1925-1937.
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Roham
authors.initials: R
authors.lastname: Parsa
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Harald
authors.initials: H
authors.lastname: Lund
authors.affiliation: Clinical Immunology, University Hospital of Zurich, Switzerland.
authors.forename: Ivana
authors.initials: I
authors.lastname: Tosevski
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Clinical Immunology, University Hospital of Zurich, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Malipiero
authors.affiliation: Institute of Neuropathology and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Germany.|Department of Neuropathology, Georg-August-University Goettingen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Beckervordersandforth
authors.affiliation: Department of Pathology and Immunology, University of Geneva, and; Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Department of Neuropathology, Georg-August-University Goettingen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gyllenberg
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Tojo
authors.initials: T
authors.lastname: James
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnecke
authors.affiliation: Neurogenetics Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.affiliation: Cardiovascular Epidemiology Unit, Department of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Clinical Immunology, University Hospital of Zurich, Switzerland.|Institute of Experimental Immunology, University of Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Clinical Immunology, University Hospital of Zurich, Switzerland.|Department of Neurology and Clinical Research Priority Program Multiple Sclerosis, University Hospital Zurich, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Suter
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Centre for Molecular Medicine, Karolinska University Hospital, Solna, Sweden. Robert.Harris@ki.se.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018417:Th1 Cells / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D000074662:NADPH Oxidase 2; D017493:Leukocyte Common Antigens
keywords: MOG-EAE; TGFβ; gene deletion; monocyte-derived dendritic cells; reactive oxygen species