Identifier

etd-11052009-141101

Degree

Doctor of Philosophy (PhD)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Dissertation

Abstract

Activation of astrocytes and microglia and the production of proinflammatory cytokines and chemokines are often associated with virus infection in the central nervous system (CNS) as well as a number of neurological diseases of unknown etiology. These inflammatory responses may be initiated by recognition of pathogen-associated molecular patterns that stimulate toll-like receptors (TLRs). Recent studies demonstrated that TLR9 family receptors play a role in neuropathogenesis and the agonists of these receptors may be used in therapeutics treatment of brain tumors and viral infections. However, we lack the basic understanding of how these receptors function in the CNS. In the present study, we examined the potential of TLR7 and TLR9 agonists to induce glial activation and neuroinflammation using an in vivo model of intracerebroventricular inoculation of these agonists in newborn mice and by in vitro stimulation of glial cells. TLR9 agonist induced a stronger neuroinflammatory response than TLR7 agonist administration in the CNS, with higher levels of proinflammatory cytokines, and the break down of the blood-brain barrier which resulted in influx of peripheral immune cells. Despite the differences in inflammation, analysis of cell types indicated involvement of similar cell types to respond to TLR7 and TLR9 agonists including ependymal cells, endothelial cells, microglia and astrocytes. This disparity in TLR7 and TLR9 activation in vivo was not observed at the in vitro level, where similar responses were observed to either agonist. The present study also determined the cross-regulatory capabilities of these receptors. Interactions between agonists were observed both in vitro and in vivo with the TLR7 agonist, imiquimod, inhibiting TLR9 agonist, CpG-ODN, or TLR9 itself, to inhibit CpG-ODN induced cytokine production. In addition to agonist interactions, an antagonistic relationship was also observed between the two receptors in microglia, with TLR7 deficiency resulting in enhanced cytokine responses to CpG-ODN stimulation. Overall, these studies demonstrate a complex interaction between TLR7 and TLR9 in regulating the initiation of innate immune responses in the brain, with TLR9 stimulation inducing more damage in the CNS than TLR7 stimulation. However, TLR7 and its agonist appear to regulate TLR9 stimulation and can diminish TLR9 agonist induced neuroinflammation.

Date

2009

Document Availability at the Time of Submission

Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.

Committee Chair

Peterson, Karin E

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