TALES OF FAT AND FURY: DECODING LIPID MESSENGERS IN IMMUNE DYSFUNCTION

Chronic inflammation is a global health challenge, driving numerous age-related diseases including neurodegeneration, yet the mechanisms underlying immune cell dysfunction in these conditions remain poorly understood. This thesis investigates the critical role of lipid metabolism in driving chronic inflammation and immune cell dysfunction, particularly focusing on glial cells. Impaired lipid metabolism, characterized by lipid droplet (LD) accumulation, is a hallmark of dysfunctional immune cells and is linked to reduced phagocytosis, activation of pro-inflammatory pathways, and senescence. We hypothesize that elucidating lipid metabolic pathways in immune cells will uncover novel immunotherapeutic targets. The first section of this thesis (Chapters 2&3) is dedicated to understanding lipidomic changes in glial cells and their functional implications in neurotrauma and neurodegeneration, aiming to identify novel immunometabolic targets for aging-associated cognitive decline and Alzheimer's Disease. The second section (Chapters 4&5) explores the development of targeted immunotherapies for cancer and pain, including novel small-molecule degraders for PD-L1 to overcome resistance to checkpoint blockade, and FPR1/PLCγ2 agonists to promote neutrophil-mediated analgesia. Finally, to address limitations of existing in vitro models, the third section (Chapters 6-8) focuses on developing improved in vitro systems, including a novel protocol for adult/aged microglia culture under serum-free conditions and a "TBI-on-a-chip" model to better recapitulate human pathophysiology and accelerate immunotherapeutic discovery for neuroinflammation. The third section also features a review article on mass spectrometry-based methods for lipidomics studies which serves as a guide for future biologists planning to incorporate lipidomics into their research.