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Degree

Doctor of Philosophy, Ohio State University, Pharmacy, 2009.

Abstract

Microglia, the resident immune cells of the brain, are critical for immune responses within the CNS. They are activated by any kind of CNS insults like ischemia and neurodegeneration, and also by Pathogen Associated Molecular Patterns (PAMPs) present on the surface of pathogens. Although their activation is critical for maintaining homeostasis within the CNS, sustained microglial activation during chronic inflammatory conditions such as infectious and neurodegenerative diseases is damaging to the surrounding cells. Beta-glucans are the major PAMPs present within the fungal cell walls that are recognized by Dectin-1 and invoke numerous intracellular events in peripheral innate immune cells. Remarkably, beta-glucans are also widely recognized for their immunomodulatory action on peripheral immune cells, but the underlying molecular mechanisms have not been fully explored. Therefore, studying microglial interaction with beta-glucans is very important to understand microglial response to fungal pathogens and immunomodulatory properties of beta-glucans in chronic inflammatory conditions of the CNS.

In an effort to understand microglial response to beta-glucans, we identified presence of Dectin-1 on the surface of cultured murine microglial cells and detected activation of Syk and Src-family kinases (SFKs) downstream of Dectin-1 in microglia. Functionally, interaction of beta-glucan with Dectin-1 resulted in phagocytosis of beta-glucan and subsequent superoxide production by microglia. Remarkably, beta-glucan-activated microglia failed to secrete significant amount of cytokines and chemokines. However, beta-glucan attenuated cytokine production by microglia in response to TLR2 and TLR4 stimulation in Dectin-1-dependent manner, and this action did not require particle internalization. Beta-glucan also suppressed TLR-mediated NF-kB activation, which may be responsible for the diminished capacity of microglia to produce cytokines in response to TLR stimulation. These results suggest that beta-glucans may be used to prevent or treat excessive microglial activation during chronic inflammatory conditions.

We also explored the molecular mechanism underlying phagocytosis of beta-glucan and subsequent ROS production by microglia. We identified Vav1 and PI3K as two important mediators downstream of Dectin-1, which are required for phagocytosis of beta-glucan and subsequent ROS production by microglia.

Collectively, our work provides insight into microglial recognition of fungal pathogens and the use of beta-glucans in modulating microglial responses during chronic inflammatory conditions.

Subject Headings

Immunology; Pharmacology

Committee / Advisors

Lakhu Keshvara (Advisor)
Lane Wallace (Committee Member)
Terry Elton (Committee Member)
Dale Hoyt (Committee Member)

Document number: osu1229705831
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=osu1229705831

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