Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
Lingzi Hong Thesis .pdf (8.07 MB)
ETD Abstract Container
Abstract Header
Act1-Mediated RNA Metabolism in IL-17-Driven Inflammatory Diseases
Author Info
Hong, Lingzi
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case162673878106271
Abstract Details
Year and Degree
2021, Doctor of Philosophy, Case Western Reserve University, Pathology.
Abstract
Interleukin 17 (IL-17, also known as IL-17A) is a key signature cytokine of Th17 cells and is also produced by innate immune cells. While IL-17 is required for host defense against extracellular microorganisms, IL-17 plays a critical role in the pathogenesis of autoimmune and inflammatory diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, and asthma. IL-17 signals through adaptor protein Act1, resulting in transcription of pro-inflammatory and neutrophil-mobilizing cytokines and chemokines, including CXCL1, TNF, IL-6 and GM-CSF. Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. We discovered that Act1 also acts as an RNA binding protein to stabilize mRNAs encoding key inflammatory proteins through a stem-loop structure element, named as SBE (SEFIR-binding element). mRNA-bound Act1 directs formation of three compartmentally distinct RNA–protein complexes (RNPs) that regulate three distinct events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro as well as IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3′ UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation. Asthma is a T cell-mediated heterogeneous disease clinically characterized by bronchial hyperresponsiveness, inflammation, and airflow obstruction. Glucocorticoids are the gold standard in asthma therapy as they can successfully control asthma in a large proportion. A substantial body of research has shown that interleukin (IL)-17A plays a critical role in the pathogenesis of severe, steroid resistant asthma. Clinical studies have also indicated that a subgroup of asthma patients responded to IL-17 signaling blockers, but the mechanism is not well understood. We showed CEBPB was the critical transcription factor that is synergistically induced by IL17-A and glucocorticoid (GC). In addition, LCN2 and SAA were also synergistically induced by IL17A and glucocorticoid (GC) through CEBPB in cultured airway cells. Mechanistically, IL17A and GC collaboratively regulated CEBPB at both transcriptional and posttranscriptional levels, which involved direct binding and stabilization of CEBPB mRNA by Act1. LCN2 and SAA may serve as LCN2 and SAA as potential circulating biomarkers for endotyping type-17 severe asthma. In one cohort study, severe asthma patients showed significantly higher plasma LCN2 and SAA as compared with healthy controls; a positive correlation was also revealed between blood IL-17A and LCN2 or SAA in patients. Taken together, our study elucidates the molecular mechanism of IL17A-Act1/CEBPB axis on steroid-resistant IL17-A targets, LCN2 and SAAs, which may serve as useful biomarkers to distinguish type-17 severe asthma endotype for anti-IL17A therapy.
Committee
Xiaoxia Li (Advisor)
Pages
177 p.
Subject Headings
Immunology
Keywords
IL-17A
;
inflammation
;
post-transcriptional regulation
;
therapeutic
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Hong, L. (2021).
Act1-Mediated RNA Metabolism in IL-17-Driven Inflammatory Diseases
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case162673878106271
APA Style (7th edition)
Hong, Lingzi.
Act1-Mediated RNA Metabolism in IL-17-Driven Inflammatory Diseases.
2021. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case162673878106271.
MLA Style (8th edition)
Hong, Lingzi. "Act1-Mediated RNA Metabolism in IL-17-Driven Inflammatory Diseases." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case162673878106271
Chicago Manual of Style (17th edition)
Abstract Footer
Document number:
case162673878106271
Download Count:
32
Copyright Info
© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.