Diet on disease onset is a critical modifier of inflammatory disease trajectory 4530

Abstract Description Obesity potently alters immune responses across a range of inflammatory contexts, but the effects of a short-term obesogenic diet, independent of significant weight gain, on immune function are not well understood. Here, we demonstrate that a short-term high-fat diet (HFD) regimen significantly increases disease severity in a model of experimental psoriasis, comparable to that observed in obese mice on long-term HFD. Notably, within this short-term regimen, we identify a critical 4-day window aligned with disease onset, sufficient to drive the majority of the exaggerated immune response. Mechanistically, this HFD-induced exaggerated response depends on NLRP3 inflammasome activation, which drives IL-1R1+ pathogenic TH17 cellular differentiation. Ablation of IL-1R1 on CD4+ T cells protects HFD-fed mice from worsened psoriatic inflammation. Finally, we observe that this rapid inflammatory remodeling has durable consequences, such that a transient bout of HFD-feeding coinciding with the initial bout of psoriasis precipitates increased disease severity on a subsequent flare, a durable effect that is dependent on CD4+ T cells. Inhibition of HFD-induced NLRP3 activation during disease onset protects mice from a more severe subsequent flare. Altogether, this work highlights the crucial role of even transient dietary changes on inflammatory disease and further posits diet on disease onset (DODO) as a critical modifier of overall inflammatory disease trajectory. Funding Sources 2023 Klein Fellowship, UCSF Diabetes Center George Coleman Discovery Fellow (Class of 2022), Graduate Division, University of California-San Francisco, CA Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)