Degree Name
PhD (Doctor of Philosophy)
Program
Biomedical Sciences
Date of Award
8-2020
Committee Chair or Co-Chairs
Mohamed Elgazzar
Committee Members
Shunbin Ning, Krishna Singh, Gary Wright, Ling Wang
Abstract
Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 and miR-181b regulate NFI-A expression via a post-transcriptional regulatory mechanism by recruiting RNA-binding proteins HuR and Ago1 to stabilize NFI-A mRNA, thus increasing its protein levels. Studies in our laboratory also showed that inflammatory mediator S100A9 accumulates in the nucleus in Gr1+CD11b+ myeloid precursors in the later phases of sepsis and is necessary for their expansion and programming into immunosuppressive MDSCs. We demonstrate here that nuclear S100A9 associates with specific transcription factors that activate miR-21 and miR-181b expressions. In our final manuscript, we uncover another layer of the mechanisms of MDSC expansion and programming. We found that long non-coding RNA (lncRNA) Hotairm1 binds to and recruits S100A9 to the nucleus to program Gr1+CD11b+ myeloid precursors into MDSCs in the later phases of sepsis. Together, our results reveal three regulatory layers involving NFI-A, S100A9 and Hotairm1 in the pathway leading to MDSCs development in sepsis and suggest that therapeutically targeting these molecular switches might improve sepsis survival.
Document Type
Dissertation - embargo
Recommended Citation
Alkhateeb, Tuqa, "Development, Expansion and Role of Myeloid-Derived Suppressor Cells in Post-Sepsis Immune Suppression" (2020). Electronic Theses and Dissertations. Paper 3787. https://dc.etsu.edu/etd/3787
Copyright
Copyright by the authors.
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Critical Care Commons, Immune System Diseases Commons, Immunity Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Immunotherapy Commons, Internal Medicine Commons, Medical Immunology Commons, Medical Microbiology Commons, Pathogenic Microbiology Commons, Pathology Commons