Type
Text
Type
Dissertation
Advisor
Carpino, Nicholas | Tsirka, Styliani-Anna E | Colognato, Holly | van der Velden, Adrianus.
Date
2015-08-01
Keywords
Neurosciences
Department
Department of Molecular and Cellular Pharmacology.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76522
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive demyelination and degeneration of neurons. As MS progresses, T cells that are normally excluded from the CNS cross the compromised blood-brain barrier due to recruitment by the resident CNS immune cells, microglia. Both microglia and T cells can promote either disease progression or disease resolution through polarization into pro- and anti-inflammatory subsets, respectively. Therapeutic approaches in MS focus on diminishing inflammation and promoting expansion of anti-inflammatory immune cell populations. Tuftsin, a stimulator of macrophage/microglial activation, is a naturally occurring tetrapeptide with the sequence T-K-P-R. In the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, infusion of tuftsin attenuates disease symptoms and promotes the anti-inflammatory response. Tuftsin's binding target is neuropilin-1 (Nrp1), a protein with critical roles in the nervous, vascular, and immune systems. In this study, we investigated whether tuftsin's beneficial effects during EAE are mediated by Nrp1. Our results show that tuftsin polarizes microglia to an anti-inflammatory phenotype specifically via Nrp1 through the canonical TGFβ pathway. Further, we report that Nrp1 promotes long, functional contacts between microglia and immunosuppressive regulatory T cells. Mice treated with tuftsin during EAE show significant reductions in disease severity, demyelination, weight loss, and inflammatory polarization in microglia. However, in mice lacking Nrp1 on macrophages/microglia, tuftsin's beneficial effects were completely abolished. Taken together, these data indicate that the Nrp1-microglial axis is the primary mediator of tuftsin's function in vivo. The results of this project provide us a fuller understanding of the mechanism of tuftsin's action during EAE, and may lead to the development of more effective disease modifying reagents for MS treatment,174 pages
Recommended Citation
Nissen, Jillian Cypser, "Tuftsin and its receptor neuropilin-1 in the attenuation of experimental autoimmune encephalomyelitis" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2429.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2429