Incomplete Recovery of Cutaneous Lipid Homeostasis during Psoriasis Remission Links Mast Cell Activation to Relapse: A Mechanistic Study

Objective: Psoriasis is a chronic inflammatory skin disease characterized by relapse. Mast cells have been implicated in early relapse, but the mechanisms driving their activation remain unclear. Therefore, this study aimed to identify key regulatory factors associated with mast cell activation in psoriasis relapse. Methods: In this mechanistic study, longitudinal skin samples were collected from patients with psoriasis receiving IL-17A inhibitor therapy at Ruijin Hospital, between 2018 and 2020. Skin transcriptomes of psoriasis patients on IL-17A inhibitor therapy were compared at baseline, remission, and relapse between those with (n=6) or without (n=8) mast cell activation features. Mechanistic findings were validated in an imiquimod-induced psoriasiform mouse model using histopathology, transcriptomics, and metabolomic analyses. In addition, in vitro assays were performed to assess the effects of candidate mechanisms on mast cell function. Results: Bulk RNA-seq identified 102 differentially expressed genes during remission, including 93 downregulated genes predominantly enriched in lipid metabolism-related pathways. Compared with healthy controls, psoriasis-associated lipid metabolism genes remained incompletely restored during remission in patients with mast cell activation but normalized in patients without mast cell activation. Enrichment scores for lipid metabolism pathways were inversely correlated with mast cell activation signatures. In the murine model, restoration of skin lipid metabolism reduced mast cell retention including IL-17A + mast cells (8.33 ± 1.22 vs. 16.33 ± 1.15 per visual field, P = 0.008), and alleviated psoriasiform inflammation upon imiquimod re-challenge (51.82 ± 1.72 vs. 94.62 ± 5.59 μm, P < 0.001). Metabolomic profiling suggested that normalization of ceramide metabolism might contribute to these effects. Furthermore, in vitro experiments showed that ceramide supplementation suppressed mast cell degranulation (6.96 ± 0.70% vs. 16.56 ± 0.33%, P = 0.02) and reduced both IL-17A uptake (2.79 ± 0.40% vs 22.57 ± 0.20%, P < 0.001) and release (519.8 ± 36.3 vs. 720.6 ± 55.4 pg/mL, P = 0.02). Conclusion: Incomplete recovery of cutaneous lipid homeostasis during remission may sustain mast cell activation and contribute to psoriasis relapse. Restoration of skin barrier-associated lipid homeostasis, particularly ceramide metabolism, may represent a translational strategy to stabilize mast cells and delay disease recurrence.