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dc.contributor.advisorLenz, Laurel L.
dc.contributor.authorCrisler, William Julius
dc.contributor.committeememberHenson, Peter
dc.contributor.committeememberMorrison, Thomas
dc.contributor.committeememberTorres, Raul
dc.contributor.committeememberWilson, Cara
dc.contributor.committeememberKeestra-Gounder, Marijke
dc.contributor.committeememberHuang, Hua
dc.date.accessioned2020-01-14T15:44:27Z
dc.date.available2020-07-06T15:44:31Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractTypes I and type II interferon (IFNα/β and IFNγ) are cytokines that are critical mediators of myeloid cell activity during immune responses. The type II IFN (IFNγ) binds IFNGR to regulate myeloid cell gene expression and drive pro-inflammatory M1-type macrophage activation that enhances antitumor and antibacterial immune responses. Type I IFNs bind their receptor (IFNAR) and induce interferon-stimulated genes required for antiviral immunity. Unlike IFNγ, type I IFNs are detrimental during intracellular bacterial infections like Listeria monocytogenes (Lm). Our lab has shown that type I IFNs increase bacterial susceptibility by inducing a rapid silencing of de novo transcription of the ifngr1 gene, decreased IFNGR1surface expression, and abrogation of macrophage IFNγ responsiveness. Here, we sought to further characterize the signaling requirements of type I IFN-induced reductions in IFNGR1. We performed a screen of small molecule inhibitors that implicated CK2α, a ubiquitous serine/threonine protein kinase. Based on this preliminary data, we designed a novel mouse model with conditional depletion of CK2α in myeloid cells (B6.mck2α-/-). Contrary to our hypothesis, primary cells from B6.mck2α-/- mice treated with IFNβ in vitro decreased IFNGR1 expression to a similar extent as wild type C57/BL6 mice. Further studies are required to understand the signaling cascade linking IFNAR ligation and the silencing of ifngr1 transcription. Next, we describe a ligand-driven mechanism that acts to calibrate myeloid cell responses to IFNγ independent of type I IFN. IFNγ reduced myeloid cell surface IFNGR in Lm-infected mice and shortly after stimulation of primary human and murine myeloid cells. Like IFNα/β, reductions in IFNGR were preceded by reduced Ifngr1 transcription. Unlike IFNα/β, IFNγ did not induce recruitment of transcriptional repressor Egr3, but instead stimulated alterations in H3K4Me3 at putative Ifngr1 enhancer sites. Strikingly, these events resulted in a blunting of IFNγ-stimulated STAT1 activation (pSTAT1). These data thus reveal a mechanism by which IFNGR1 abundance and myeloid cell sensitivity to IFNγ can be modulated in the absence of type I IFNs. The existence of distinct ligand-dependent and -independent mechanisms to regulate macrophage IFNGR1 availability suggests that calibration of macrophage IFNGR1 abundance plays an important role in restraining excessive macrophage activation following encounters with “non-dangerous” inflammatory stimuli. These findings have implications for strategies geared at exploiting myeloid cell activity to treat infections, cancer, and autoimmune diseases.
dc.identifierCrisler_ucdenveramc_1639D_10677.pdf
dc.identifier.urihttps://hdl.handle.net/10968/4764
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 07/06/2020
dc.subject.meshImmunity, Innate
dc.subject.meshMacrophages
dc.subject.meshInterferons
dc.subject.meshInflammation
dc.titleRegulation of myeloid cell IFNGR1 by types I and II interferon, The
dc.typeThesis
dcterms.embargo.expires2020-07-06
thesis.degree.disciplineImmunology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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