Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

• Published in: Cell reports (Cambridge) 2017-01, Vol.18 (1), p.198-212
• Main Authors: Gao, Han, Danzi, Matt C., Choi, Claire S., Taherian, Mehran, Dalby-Hansen, Camilla, Ellman, Ditte G., Madsen, Pernille M., Bixby, John L., Lemmon, Vance P., Lambertsen, Kate L., Brambilla, Roberta
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation; Chronic Disease; CX3C Chemokine Receptor 1 - metabolism; cytokines; Demyelinating Diseases - genetics; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Encephalomyelitis, Autoimmune, Experimental - etiology; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Gene Deletion; Gene Expression Regulation; Homeostasis - genetics; Inflammation - pathology; macrophages; Macrophages - metabolism; Mice, Inbred C57BL; microglia; Microglia - metabolism; multiple sclerosis; Myelin Sheath - metabolism; neuroinflammation; Neuroprotection; Phenotype; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - metabolism; Sequence Analysis, RNA; Spinal Cord - pathology; T-Lymphocytes - cytology; T-Lymphocytes - immunology; TNF signaling; Transcriptome - genetics; tumor necrosis factor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.083

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. [Display omitted] •TNFR2 has opposing functions in microglia and monocytes/macrophages in EAE•Microglial TNFR2 mediates protective responses at EAE onset•Monocyte/macrophagic TNFR2 is detrimental in EAE by driving autoimmune activation Gao et al. uncover a dichotomy of functions for microglial versus monocyte/macrophagic TNFR2 in EAE pathophysiology. They demonstrate that TNFR2 in microglia is protective and provides signals to contain neuroinflammation, whereas TNFR2 in monocytes/macrophages is detrimental and drives immune activation and EAE initiation.