Abstract
High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFDs on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs-saturated, monounsaturated, omega-6, and omega-3 fats-were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1β-producing macrophages, IL-17A-producing γδ T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1β/IL-17A signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1β/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1β/IL-17 axis, offering insights into the interplay between dietary fats, obesity, and psoriasis.