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IL-17-MEDIATED TRANSCRIPTION FACTORS IN DISEASE

Taylor, Tiffany, C (2023) IL-17-MEDIATED TRANSCRIPTION FACTORS IN DISEASE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Interleukin-17 is a pro-inflammatory cytokine essential for defense against extracellular microorganisms but also contributes to the pathogenesis of many autoimmune diseases. Candida albicans is a commensal fungus that colonizes mucosal tissues and is the causative agent of oropharyngeal candidiasis (OPC). Defects in IL-17 signaling increase susceptibility to OPC in both humans and mice. During OPC and autoimmunity, several TFs are induced in an IL-17-dependent manner, including IκBz and Arid5a. There are also other TFs that are not inducible but also function downstream of the IL-17 receptor to orchestrate the cytokine response. Moreover, certain IL-17 activated TFs can associate with RNA and regulate posttranscriptional expression of target genes. This dissertation focuses on TFs operating in the IL-17 signaling pathway. In chapter 3, I show thatIκBz (Nfkbiz) is upregulated during OPC in an IL-17-dependent manner. Deletion of Nfkbiz renders mice susceptible to OPC and acts in the nonhematopoietic compartment. In mice lacking Nfkbiz in suprabasal oral epithelial cells (OECs), there was a markedly impaired IL-17 gene signature profile that revealed a prominent IκBz gene target to be b-defensin (BD)-3 (Defb3), known to be an essential antifungal antimicrobial peptide. In human OECs, IκBz was required for IL-17 regulation of BD2 (DEFB4A, orthologue of mouse Defb3) through the DEFB4A promoter. Additionally, IκBz regulated early growth response 3 (EGR3), which was dispensable for IL-17 signaling but required for C. albicans induction of BD2/DEFB4A.
Arid5a is another IL-17-inducible TF that regulates IκBz expression. In chapter 4, I show that Arid5a is required for pathology an IL-17-driven autoimmune model of multiple sclerosis but is dispensable in models of candidiasis. Finally, I show that a related TF, Arid5b, functions in the IL-17 pathway to negatively regulate IL-17-target genes. My findings in this dissertation cumulatively highlight bifurcation of the IL-17 receptor pathway with respect to IL-17 protective host defense versus pathological inflammation in autoimmunity.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Taylor, Tiffany, Ctit23@pitt.edutit230000-0002-4971-3728
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBiswas, Parthapartha.biswas@pitt.edu
Committee MemberBinder, Robertrjb42@pitt.edu
Committee MemberAtianand, Maninjayatianand@pitt.edu
Committee MemberMorel, Penelopemorel@pitt.edu
Thesis AdvisorGaffen, Sarahsarah.gaffen@pitt.edu
Date: 8 December 2023
Date Type: Publication
Defense Date: 8 August 2023
Approval Date: 8 December 2023
Submission Date: 18 August 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 153
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: IL-17, C. albicans, IkappaBzeta, OPC
Date Deposited: 08 Dec 2023 16:37
Last Modified: 08 Dec 2023 16:37
URI: http://d-scholarship.pitt.edu/id/eprint/45351

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