FABP5 in Skin Macrophages Mediates Saturated Fat-Induced IL-1β Signaling in Obesity-Associated Psoriasis Development

Summary High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFD-induced obesity 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-17 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. Highlights Saturated, but not unsaturated, high-fat diets (HFDs) drive the development of obesity-associated psoriasis. Saturated fats enhance IL-1β/IL-17 signaling in psoriatic skin. FABP5 mediates saturated fat-induced IL-1β signaling by promoting ATP production and release. Deletion of FABP5 in macrophages alleviates the development of saturated HFD-associated psoriasis.