Brief high-fat diet exposure imprints TH17-driven inflammatory memory in skin independent of obesity

Obesity alters immune responses across inflammatory contexts; however, whether brief dietary changes influence immune function independent of weight gain remains unclear. Here, we demonstrate that transient high-fat diet (HFD) exposure during the onset of psoriasiform inflammation markedly exacerbates disease severity in lean mice. Mechanistically, HFD rapidly increases neutrophil accumulation and NLRP3-dependent IL-1β production in lesional skin, promoting IL-1R1⁺ pathogenic TH17 differentiation and establishment of a chromatin-primed tissue-resident memory CD4⁺ T cell population. Transient HFD exposure during disease onset durably amplifies inflammatory recall responses upon rechallenge, despite subsequent dietary normalization. These findings identify diet on disease onset (DODO) as a critical modifier of inflammatory disease trajectory. Single-nucleus ATAC-seq of CD4⁺ T cells from recovered skin following diet-modulated IMQ-induced inflammation Transient high-fat diet (HFD) exposure during the onset of psoriasiform inflammation induces durable transcriptional and epigenomic remodeling in CD4⁺ T cells. To define chromatin accessibility programs associated with inflammatory memory, we performed single-nucleus ATAC sequencing (snATAC-seq) of sorted CD4⁺ T cells isolated from ear skin following recovery from imiquimod (IMQ)-induced inflammation in mice fed either low-fat diet (LFD) or HFD. These data enable identification of differentially accessible regulatory elements and chromatin states associated with diet on disease onset (DODO)-driven inflammatory memory.