Helminth-Derived Immunomodulators as Potential Therapies Against Adipose Tissue Inflammation in Obesity

Obesity is a global health crisis and a key driver of metabolic dysfunction, increasing the risk of morbidity and mortality. Despite decades of research, obesity treatments have largely overlooked immune dysregulation, particularly the chronic low-grade inflammation that underlies metabolic disease. Addressing this inflammatory component is crucial for developing more effective long-term strategies to combat obesity and its associated health risks. A central player in obesity-associated inflammation is interleukin-33 (IL-33), a cytokine that promotes type 2 immune responses, counteracting metabolic inflammation and protecting against obesity-related pathology. While IL-33 is considered protective in obesity, its primary role is in driving type 2 immune responses, which are essential for immunity to helminths. Notably, obesity is most prevalent in regions where helminth infections are rare, and emerging evidence suggests that helminths may provide protection against the inflammation associated with metabolic disease. This raises the question of whether helminths play a causal role in modulating metabolic inflammation. IL- 33, which bridges helminth immunity and metabolic regulation, provides a potential link between these two conditions. This thesis investigates how IL-33 responses are regulated and their contribution to obesity-associated inflammation. Using plasma samples from the Edinburgh Obesity Biobank, soluble IL-33 receptors are examined in lean and obese individuals to assess their relationship with obesity metrics. Beyond human studies, a mouse model of diet-induced obesity and helminth infection is used to explore how the hookworm Heligmosomoides polygyrus bakeri shapes IL-33 responses and impacts adipose tissue immunology. Finally, helminth- derived IL-33 modulators are investigated to determine whether they can restore type 2 immune responses in obesity. This work contributes to a deeper understanding of IL-33 regulation in obesity and explores the potential for helminth-derived immunomodulatory strategies to counter obesity-associated inflammation.