Phenylalanine Exacerbates Psoriasiform Inflammation by Activating Dendritic Cells and Th17 Polarization via NF-κB

Metabolic dysregulation is increasingly recognized as a significant contributor to the pathogenesis of psoriasis, a chronic immune-mediated inflammatory disorder. Despite this, the precise mechanistic roles of specific amino acid perturbations in driving the disease remain poorly understood. Current treatments often target immune pathways but may not fully address underlying metabolic drivers, leaving a gap for adjunctive, non-toxic strategies. Understanding how specific metabolites like phenylalanine influence immune cell activation and inflammatory cascades, particularly the IL-17 signaling axis, could uncover novel therapeutic targets.

Researchers conducted comprehensive metabolomic profiling in psoriatic mice to identify altered amino acid levels. They then investigated the impact of dietary phenylalanine on imiquimod-induced psoriasiform skin inflammation. Mice were subjected to either a high-phenylalanine diet or dietary restriction of phenylalanine, and some received L-type amino acid transporter inhibitors. The primary endpoint was the severity of skin inflammation. Mechanistically, transcriptome sequencing of dendritic cells was performed to identify phenylalanine's effects on gene expression and inflammatory pathways, specifically focusing on NF-κB signaling and T helper 17 cell differentiation.

Metabolomic profiling revealed a marked accumulation of phenylalanine in both the circulation and skin lesions of psoriatic mice. A high-phenylalanine diet significantly exacerbated psoriasiform skin inflammation in the imiquimod-induced model. Conversely, dietary restriction of phenylalanine or administration of L-type amino acid transporter inhibitors effectively alleviated skin inflammation. Transcriptome sequencing of dendritic cells identified phenylalanine as a potent metabolic trigger, demonstrating that high phenylalanine levels alone significantly elevated the baseline expression of notable pro-inflammatory cytokines. This inflammatory response was further amplified in the presence of imiquimod. The study determined that this pro-inflammatory effect was mediated through the NF-κB signaling pathway, which subsequently promoted the differentiation of T helper 17 cells. This mechanistic link highlights a critical role for phenylalanine in driving the inflammatory cascade.

Phenylalanine directly activates dendritic cells via NF-κB, leading to increased pro-inflammatory cytokine expression and Th17 cell polarization, thereby exacerbating psoriasiform inflammation.