All ETDs from UAB

Advisory Committee Chair

Etty Benveniste

Advisory Committee Members

Hongwei Qin

Jessy S Deshane

Laurie E Harrington

Hui Hu

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway plays a critical role in cytokine-mediated responses in both innate and adaptive immunity, and dysregulation of the JAK/STAT pathway is linked to many inflammatory disorders. Multiple Sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system, and both innate and adaptive immunity are involved in disease progression. STAT3 signaling is critically involved in MS pathology and is negatively regulated by Suppressor Of Cytokine Signaling 3 (SOCS3). Both increased STAT3 activation and reduced SOCS3 expression are observed in immune cells from patients with MS. Although the role of STAT3/SOCS3 signaling in MS and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE), has been studied for years, their role in myeloid cells still requires further investigation. Our lab previously demonstrated that mice with Socs3 deficiency in myeloid cells (Socs3ΔLysM) leads to a severe, non-resolving, brain-targeted form of EAE. Furthermore, brain-targeted EAE correlates with preferential neutrophil infiltration in the cerebellum. However, the molecular mechanisms by which neutrophils induce brain-targeted EAE in Socs3ΔLysM mice is not clear. In this project, I first demonstrated that neutrophils exhibit a hyper-activated phenotype with enhanced production of reactive oxygen species (ROS) in Socs3ΔLysM mice at peak of EAE. Neutralization of ROS in vivo delayed the onset of EAE, and reduced both incidence and severity of brain-targeted EAE. I also demonstrated that Socs3 deficiency leads to G-CSF hypersensitivity in neutrophils via JAK1/STAT3 activation, and G-CSF induces a unique gene expression profile in Socs3-deficient neutrophils. Finally, G-CSF neutralization suppressed brain-targeted atypical EAE in Socs3ΔLysM mice. Overall, my findings document the protective role of myeloid SOCS3 in MS/EAE by suppressing overt STAT3 activation upon G-CSF stimulation. My data support previous clinical reports for the deleterious role of G-CSF in MS and other neuroinflammatory diseases. Overall, my studies suggest that targeting aberrant STAT3/SOCS3 pathway activation could be a promising approach for developing novel therapies for neuroinflammatory diseases.

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