FABP5 in skin macrophages mediates saturated fat-induced IL-1β signaling in psoriatic inflammation
Jianyu Yu, Jiaqing Hao, Matthew S. Yorek, Xingshan Jiang, Anthony M. Avellino, Shanshan Liu, Xiaochun Han, Jonathan Shilyansky, Zhaohua Wang, Yuhang Wang, Zizhen Kang, Ali Jabbari, Bing Li
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.