Abstract
Abstract Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation, accompanied by significant alterations in immune homeostasis. Dysregulation of fatty acid metabolism, particularly involving polyunsaturated fatty acids (PUFAs), has been implicated in the pathogenesis of psoriasis; however, the precise relationship between metabolic dysregulation and inflammatory responses in psoriasis remains poorly understood. In this study, we investigated the role of Δ6 desaturase/fatty acid desaturase 2 (FADS2), the first and rate-limiting enzyme in PUFA synthesis, in psoriasis and its underlying mechanisms. We first demonstrate that the expression of FADS2 was significantly decreased in the epidermis of the skin lesions from psoriasis patients and imiquimod (IMQ)-induced psoriasis mouse model. Treatment with IL-23 inhibitor Guselkumab restored FADS2 expression in the epidermis of lesional skin of psoriasis patients. Furthermore, silencing FADS2 in cultured human keratinocytes resulted in the upregulation of multiple chemokines and antimicrobial peptides under M5 condition (a psoriasis-like inflammatory condition). Mechanically, suppression of FADS2 disrupted PUFA metabolism with an inhibition of the desaturation of omega-3 fatty acids to the anti-inflammatory metabolite docosahexaenoic acid (DHA), thereby contributing to the inflammatory processes through the NF-κB pathway. Additionally, we found that FADS2 expression in keratinocytes was dependent on peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor involved in lipid metabolism across various tissues. A reduction in the PPARα-FADS2 axis was observed in the lesional skin of psoriasis patients and IMQ-induced psoriasis mouse model. In vivo experiments revealed that silencing FADS2 via the topical application of small interfering RNA (siRNA) exacerbated IMQ-induced psoriasis-like dermatitis, whereas enhancing FADS2 expression through PPARα activation with its agonist WY14643 led to a significant attenuation of psoriasis inflammation. These findings identify PPARα as a critical regulator of FADS2 expression in psoriasis and elucidate the contribution of FADS2 to fatty acid reprogramming and inflammatory responses in psoriasis. Therefore, FADS2 and PPARα emerge as promising therapeutic targets for managing psoriasis.
Published Version
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