Amatya, Nilesh
(2019)
POST-TRANSCRIPTIONAL CONTROL OF IL-17 RECEPTOR-MEDIATED INFLAMMATION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Interleukin-17A (commonly known as IL-17) is a pro-inflammatory cytokine critical in host
defense against microbial pathogens. However, dysregulated IL-17 receptor signaling drives
many autoimmune conditions including psoriasis, multiple sclerosis and autoimmune glomerulonephritis. Activation of inflammatory gene transcription through NF-κB is one of the most well-characterized IL-17 signaling pathways. However, IL-17 is consistently found to be a modest activator of transcription in experimental settings. Thus, the profound biological functions of IL-17 in vivo are often attributed to post-transcriptional control of IL-17 target gene expression, but the fundamental mechanisms remain largely underexplored. In this dissertation, I have focused on understanding the basic principles underlying IL-17-induced post-transcriptional regulation of inflammatory genes. Here, I describe two novel RNA-binding proteins (RBP) that promote IL-17-induced inflammation. In chapter 3, I have focused on
understanding how IL-17 promotes inflammation by regulating mRNA stability and mRNA translation through an RNA-binding protein called AT-rich interactive domain-containing protein 5A (Arid5a). Arid5a stabilizes mRNAs encoding IL-17-driven genes such as Il6, Cxcl1
and Cxcl5 by directly binding to their 3’UTR. Arid5a also enhances mRNA translation of key transcription factors such as C/EBPβ and IκBξ, which in turn facilitate transcription of IL-17 target genes. In chapter 4, I identified another RBP, which acts as an activator of IL-17 signaling. This RBP upregulates expression of
IL-17-dependent genes at least in part by triggering NF-κB. Mice deficient in this RBP are less
susceptible to IL-17-dependent autoimmune models such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune glomerulonephritis (EAGN).
Interestingly, this RBP does not affect Th17 differentiation in vivo or in vitro. Using radiation
chimeras, I found that this RBP functions dominantly in the non-hematopoietic compartment to induce kidney damage during EAGN. These results are consistent with a model in which this novel RBP positively regulates IL-17 mediated signaling rather than affecting Th17 cell
differentiation. Therefore, my dissertation research has deepened our understanding of how RBPs play essential roles in controlling IL-17 signaling post-transcriptionally. Understanding these mechanisms would be beneficial for designing oligonucleotides or small molecule inhibitors that can restrain RBP-mRNA interactions to dampen inflammation during autoimmune
conditions.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
10 October 2018 |
| Approval Date: |
3 January 2019 |
| Submission Date: |
28 November 2018 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
178 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Interleukin-17, Arid5a, RNA-binding proteins, post-transcriptional gene regulation |
| Date Deposited: |
03 Jan 2019 20:03 |
| Last Modified: |
03 Jan 2024 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35651 |
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