Exploring the Link Between Extracellular Vesicle-Associated Inflammation in Obesity and Sepsis Outcomes

About This Grant

Summary Obesity, now at pandemic levels, significantly increases the risk of numerous comorbidities, including sepsis- a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. A major contributor to the obesity epidemic is the widespread consumption of ultra-processed foods (UPFs), which promote excessive nutrient intake and are linked to chronic metabolic and inflammatory disturbances. These conditions activate nutrient-sensing pathways that connect nutrient excess with systemic inflammation, contributing to obesity-associated immune dysregulation. We hypothesize that obesity-associated metabolic stress enhances the production of pro-inflammatory small extracellular vesicles (sEVs), which in turn drive systemic inflammation and contribute to organ injury during sepsis. Small EVs are released by various cell types into the extracellular space and circulate in body fluids, where they are taken up by local or distant recipient cells. Our data from obese pediatric patients and healthy controls suggest that obesity imparts inflammatory traits to circulating sEVs. These vesicles, when internalized by immune cells such as macrophages, modulate inflammatory gene expression. Preliminary findings further indicate that the RNA cargo within sEVs plays a central role in regulating these immune responses. In this study, we will: 1. Define the upstream regulatory pathways that confer pro-inflammatory properties to liver-derived sEVs and evaluate their impact on sepsis outcomes in pre-clinical models. 2. Identify key molecular mediators in macrophages that drive sEV-induced inflammatory responses. Although sEV biology is rapidly evolving, the clinical implications of these vesicles remain largely unexplored. Leveraging our unique mouse models, human sEV samples, and human induced pluripotent stem cell (iPSC)- derived hepatocytes and macrophages, we aim to uncover how liver-derived sEVs shape systemic immune responses and drive organ dysfunction in sepsis. This work will clarify how obesity amplifies inflammation during critical illness and may identify novel biomarkers and therapeutic targets.