Publication Date

2017-01-11

Availability

Open access

Embargo Period

2017-01-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2016-12-19

First Committee Member

Roberta Brambilla

Second Committee Member

Carlos T. Moraes

Third Committee Member

Daniel J. Liebl

Fourth Committee Member

Jae K. Lee

Fifth Committee Member

Lawrence Wrabetz

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.

Keywords

Multiple Sclerosis; Microglia; Macrophage; Neuroinflammation; TNF

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