Publication Date

12-2021

Date of Final Oral Examination (Defense)

11-5-2021

Type of Culminating Activity

Dissertation

Degree Title

Doctor of Philosophy in Biomolecular Sciences

Department

Biology

Supervisory Committee Chair

Richard S. Beard Jr., Ph.D.

Supervisory Committee Co-Chair

Cheryl L. Jorcyk, Ph.D.

Supervisory Committee Member

Daniel Fologea, Ph.D.

Abstract

Integrity of the brain microvessels that form the blood-brain barrier (BBB) is maintained through fine-tuned regulation of endothelial tight junction proteins, chiefly represented by claudin 5 and the tight junction-associated MARVEL protein (TAMP) occludin. Under proinflammatory conditions in autoimmune-mediated multiple sclerosis (MS), autoreactive effector T cells are activated in white matter regions of the brain and spinal cord and release cytokines to recruit circulating neutrophils that, in turn, release neurotoxic substances. Lack of tight junctions in peripheral blood vessels allows neutrophils to exit blood vessels unhindered, but BBB tight junctions must first be downregulated before neutrophils can transmigrate into the brain. The resulting loss of BBB integrity initiates a pathogenic feedback loop propagating the inflammatory injury. Understanding the established relationship between neutrophilia and BBB dysfunction in neuroinflammation, I set out to better define the cellular contributions behind this pathology. Early on, I identified increased circulating levels of the cytokine oncostatin M (OSM) concomitant with a pathogenic increase in OSM+ neutrophil counts during the effector phase of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Next, I found that BBB endothelial cells selectively downregulate occludin, but not claudin 5, after stimulation with OSM. To dissect the mechanisms responsible, I identified that fewer neutrophils are able to cross BBB endothelial monolayers lacking OSMRβ, the cognate OSM receptor. Finally, in OSMRβ-knockout mice, I found a rescue in symptoms, BBB permeability to small molecules, and occludin expression during the effector phase of EAE. Overall, this work identifies a novel role for OSM as an inflammatory cytokine released by neutrophils that specifically regulates BBB TAMPs during autoimmune-mediated neuroinflammation.

Comments

Travis S. Wertz, ORCID: 0000-0002-2886-5634

DOI

https://doi.org/10.18122/td/1902/boisestate

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