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

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): 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
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.

Graphical abstract

Teaser

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.


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