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
Recommended Citation
Gao, Han, "Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis" (2017). Open Access Dissertations. 1783.
https://scholarlyrepository.miami.edu/oa_dissertations/1783