All ETDs from UAB

Advisory Committee Chair

Alexander J Szalai

Advisory Committee Members

Anupam Agarwal

Jessy S Deshane

Chander Raman

Amy S Weinmann

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

C-reactive protein (CRP) is an evolutionarily conserved pattern recognition molecule that was first characterized for its participation in the acute phase response to bacterial infection. In the last 90 years, knowledge of CRP biology in innate immunity has expanded significantly. CRP is known to bind and activate the classical pathway of complement, to opsonize bacteria and inflamed tissue, and to modulate myeloid cell functions. CRP is normally present in the blood at low levels with its biosynthesis and serum concentration rapidly rises upon systemic inflammation. For example, high levels of serum CRP are found following acute kidney injury (AKI) in both humans and human CRP transgenic mice (CRPtg) undergoing a model of AKI wherein they experience worse outcomes than their WT counterparts. Additional work showed that during AKI, CRP mobilizes a population of leukocytes: myeloid derived cells with suppressor functions (MDSC) that appeared to be responsible for CRP’s harmful effects. My dissertation research sought to address how CRP modulates myeloid cell development, maturation, and function and whether MDSC actions could directly injure the renal epithelium, the major cell type damaged during AKI. I open with an extensive overview of CRP and how my dissertation project fits within the larger context of CRP research. Next, I introduce AKI epidemiology and our experimental understanding of its cellular pathology and myeloid cell involvement. I also included a brief overview of myelopoiesis as this is essential for understanding MDSC biology. My chapters are organized in order to show i) CRP regulates dendritic cell development, function, maturation, and its consequences in autoimmunity, ii) CRP promotes MDSC development and suppressive functions, and iii) MDSCs impair renal epithelial cell cycling. I end with a discussion of a newly formed thesis: CRP is an evolutionarily conserved molecule that modulates the functional phenotype of myeloid cells during their development from bone marrow progenitors. Further, I overview known CRP effects on differentiated myeloid cells, its roles in autoimmunity, a hypothesis of its effects in AKI in light of the data presented herein, and the future of CRP myeloid modulation in cancer.

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