title: Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis.
abstract: In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here, we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Matt C
authors.initials: MC
authors.lastname: Danzi
authors.affiliation: Columbia University, New York, NY 10027, USA.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Choi
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mehran
authors.initials: M
authors.lastname: Taherian
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Dalby-Hansen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark.
authors.forename: Ditte G
authors.initials: DG
authors.lastname: Ellman
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark.
authors.forename: Pernille M
authors.initials: PM
authors.lastname: Madsen
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cellular and Molecular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Bixby
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Center for Computational Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Vance P
authors.initials: VP
authors.lastname: Lemmon
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C 5000, Denmark; Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense C 5000, Denmark; Department of Neurology, Odense University Hospital, Odense C 5000, Denmark.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
authors.affiliation: The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: r.brambilla@miami.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism; D049109:Cell Proliferation; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D000066829:Neuroprotection; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D059467:Transcriptome / Q000235:genetics
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
keywords: TNF signaling; cytokines; macrophages; microglia; multiple sclerosis; neuroinflammation; tumor necrosis factor