Date of Award

Summer 8-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Activated macrophages produce genotoxins such as reactive oxygen and nitrogen intermediates that are critical for the eradication of pathogens. Here we show that one of these agents, nitric oxide (NO), damages macrophage genomic DNA, resulting in the activation of DNA damage responses (DDR). The DDR is primarily initiated through DNA double-strand break (DSB) intermediates and depends on the PI3-like kinases ATM and DNA-PKcs. In response to Listeria monocytogenes infection, ATM and DNA-PKcs regulate a tissue-specific genetic program that includes the expression of inflammatory cytokines, chemokines and cell surface receptors, several of which are critical for cell migration during immune responses to bacterial infection. These kinases also regulate inflammasome activation and production of the inflammatory cytokines IL-1β and IL-18. Due to the near-complete block in IL-18 production by DNA-PKcs- deficient macrophages, these cells are unable to optimally stimulate NK cells to produce IFN-γ, which is important for controlling early L. monocytogenes infection. These findings establish DNA damage, and the initiation of DDR by this damage, as important signaling intermediates in the innate immune responses mediated by macrophages.

Language

English (en)

Chair and Committee

Barry Sleckman

Committee Members

Marco Colonna, Michael Diamond, Brian Edelson, Eugene Oltz, Emil Unanue

Comments

Permanent URL: https://doi.org/10.7936/K7W09462

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