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

Han Gao, Matt C. Danzi, Claire S. Choi, Mehran Taherian, Camilla Dalby-Hansen, Ditte G. Ellman, Pernille M. Madsen, John L. Bixby, Vance P. Lemmon, Kate L. Lambertsen, Roberta Brambilla
2017 Cell Reports  
Graphical Abstract Highlights d TNFR2 has opposing functions in microglia and monocytes/ macrophages in EAE d Microglial TNFR2 mediates protective responses at EAE onset d Monocyte/macrophagic TNFR2 is detrimental in EAE by driving autoimmune activation SUMMARY 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
more » ... 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.
doi:10.1016/j.celrep.2016.11.083 pmid:28052249 pmcid:PMC5218601 fatcat:fncru4tgcnddxdtkfjo4sfna6e