Intestinal Epithelial Cell Intrinsic IL-1R Signaling in Host Defense and Inflammation

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dc.contributor.advisorSatterthwaite, Anne B.en
dc.contributor.committeeMemberPasare, Chandrashekharen
dc.contributor.committeeMemberKoh, Andrew Y.en
dc.contributor.committeeMemberZaki, Hasanen
dc.creatorOvercast, Garrett Rayen
dc.creator.orcid0000-0002-4402-5635
dc.date.accessioned2024-06-07T19:15:12Z
dc.date.available2024-06-07T19:15:12Z
dc.date.created2022-05
dc.date.issued2022-05
dc.date.submittedMay 2022
dc.date.updated2024-06-07T19:15:12Z
dc.descriptionPages viii-xix are misnumbered as pages vi-xvii.en
dc.description.abstractIntestinal epithelial cells (IECs) constitute a critical first line of defense against microbes by providing a physical barrier and producing antimicrobial peptides (AMPs) and cytokines. While IECs are known to respond to various microbial signals, the precise upstream cues regulating diverse IEC responses are not clear. Here we discover a dual role for IEC intrinsic interleukin-1 receptor (IL-1R) signaling in regulating both intestinal homeostasis and inflammation. Specifically, absence of IL-1R in epithelial cells abrogates a homeostatic antimicrobial program including production of AMPs. Mice deficient for IEC intrinsic IL-1R are unable to clear Citrobacter rodentium and have impaired AMP gene expression during infection. Mechanistically, IL-1R signaling enhances IL-22R induced STAT3 phosphorylation in IECs leading to elevated production of AMPs. A similar synergy between IL-1β and IL-22 was found in human IECs. We find that IL-1R signaling on IECs directly induces expression of chemokines as well as genes involved in the production of reactive oxygen species in IECs. Absence of IL-1R in IECs protected mice from chemically induced colitis, suggesting that IEC intrinsic IL-1R signaling contributes to worsened inflammation and pathology during acute inflammation. Our findings establish a protective role for IEC intrinsic IL-1R signaling in combating infections, and a detrimental role of IEC intrinsic IL-1R signaling during colitis induced by epithelial damage.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1438579289
dc.identifier.urihttps://hdl.handle.net/2152.5/10302
dc.language.isoenen
dc.subjectEpithelial Cellsen
dc.subjectHomeostasisen
dc.subjectIntestinal Mucosaen
dc.subjectReceptors, Interleukinen
dc.titleIntestinal Epithelial Cell Intrinsic IL-1R Signaling in Host Defense and Inflammationen
dc.typeThesisen
dc.type.materialtexten
local.embargo.lift2024-06-01
local.embargo.terms2024-06-01
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineImmunologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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