Abstract
Saturated fats in high-fat diets (HFDs) have been associated with increased risk and severity of psoriasis. However, the underlying cellular and molecular mechanisms remain to be further defined. Here, using a unique mouse strain with keratinocyte-specific deletion of fatty acid-binding protein 5 (FABP5) (Fabp5f/fKrt6a-Cre), we reported that keratinocyte FABP5 deletion significantly attenuated saturated HFD-exacerbated psoriatic symptoms. Immunological analyses demonstrated that FABP5 specific deletion in keratinocytes selectively reduced skin TCR γ δ dim cell accumulation and IL-17A production. Further skin bulk-RNA and single-cell RNA sequence analyses showed a strong association of keratinocyte FABP5 with increased activation of mitogen-activated protein kinase (MAPK) pathways under saturated HFD-induced obesity. Mechanistically, saturated fatty-acids (SFAs) induce FABP5-dependent MAPK activation and CCL20 production in keratinocytes, promoting the recruitment and activation of IL-17-producing γδ T cells in the skin. Together, these findings suggest a previously undefined FABP5/MAPK/CCL20 signaling axis that links saturated fats to exacerbated psoriatic inflammation.