Graduation Semester and Year

Fall 2025

Language

English

Document Type

Thesis

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Dr. Subhrangsu S. Mandal

Second Advisor

Dr. Kayunta Johnson Winters

Third Advisor

Dr. He Dong

Fourth Advisor

Dr. Kevin Schug

Abstract

Inflammation, a manifestation of immune activation, serves as both a protective and pathological mechanism. When unresolved, chronic inflammation contributes to the onset and progression of multiple disorders including cardiovascular diseases, autoimmune syndromes, neurodegeneration, and cancer. The intricate interplay between immune signaling and metabolic regulation forms a critical aspect of immune homeostasis. Tryptophan and its catabolic enzyme Indoleamine 2,3-dioxygenase 1 (IDO1) play pivotal roles in linking metabolism to immune tolerance and inflammation. Recent advances reveal that noncoding RNAs, especially long noncoding RNAs (lncRNAs), exert extensive regulatory functions across immune and metabolic processes. Despite growing recognition of their importance, the mechanistic contribution of lncRNAs to inflammatory and metabolic integration remains largely unexplored. This thesis investigates the molecular and functional interconnections among inflammation, immunity, and tryptophan metabolism, emphasizing the emerging role of lncRNAs in immunometabolic regulation.

Chapter 1 provides an extensive overview of the immune system, inflammatory mechanisms and link to metabolism. Persistent inflammation is linked to diverse organ pathologies through dysregulated signaling pathways, notably NF-κB, MAPK, and JAK-STAT. These pathways are metabolically controlled by glucose, lipid, and amino acid turnover, with tryptophan metabolism serving as a crucial immunomodulatory junction. The chapter underscores the expanding landscape of noncoding RNA biology, particularly long noncoding RNAs, which regulate gene expression via structural interactions with proteins and nucleic acids. It sets the conceptual foundation for exploring the role of lncRNAs in immune-metabolic regulation through the example of hLinfRNA7.

Chapter 2 focuses on macrophage function, along with crosstalk between tryptophan metabolism and cholesterol homeostasis. It demonstrates that inflammation impairs cholesterol homeostasis by downregulating the HDL receptor SR-BI via NF-κB activation. The study identifies IDO1 as a key modulator linking inflammatory signaling to cholesterol uptake, revealing an IDO1–NF-κB–SR-BI regulatory axis crucial to macrophage lipid metabolism.

Chapter 3 identifies and characterizes hLinfRNA7, an inflammation-associated lncRNA antisense to IDO1. hLinfRNA7 induction by LPS enhances cytokine expression and NF-κB activity and lowers IDO1 and kynurenine levels. Reciprocal regulation between hLinfRNA7 and IDO1 establishes a bidirectional feedback mechanism. The RNA-binding protein YBX1 interacts with hLinfRNA7 to coordinate cytokine and metabolic outcomes, defining an hLinfRNA7–YBX1–IDO1 axis that integrates inflammatory and metabolic signaling.

Chapter 4 extends these findings to hepatic inflammation under estrogen-deficient conditions. Using ovariectomized rats, it shows that estrogen loss activates hepatic IDO1/TDO2, elevates cytokine levels, represses SR-BI, and disrupts cholesterol metabolism—effects reversed by estradiol treatment. This reveals an estrogen–IDO1–SR-BI network that underlies postmenopausal inflammatory dyslipidemia.

Collectively, the thesis uncovers functions of a newly identified lncRNA hLinfRNA7 in IDO1- mediated tryptophan catabolism and immune signaling, and how estrogen deficiency alters hepatic inflammatory and metabolic homeostasis. Together, these studies identify novel molecular axes that coordinate immune signaling with metabolic balance and highlight potential therapeutic avenues for inflammation-associated metabolic diseases.

Keywords

Long noncoding RNAs, Inflammation, Macrophage, Metabolism, Tryptophan, Cholesterol, IDO1, Kynurenine

Disciplines

Biochemistry | Cardiovascular Diseases | Immunity | Molecular Biology

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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Available for download on Thursday, December 09, 2027

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