Targeting PTGDS inhibits pro-inflammatory fibroblasts associated with skin fibrosis in systemic sclerosis

Abstract Objectives Immune dysregulation significantly contributes to skin fibrosis in systemic sclerosis (SSc), with pro-inflammatory fibroblasts playing a pivotal role in this process. Prostaglandin D2 synthase (PTGDS) has garnered interest due to its enriched expression in pro-inflammatory fibroblasts associated with skin fibrosis. This study aims to elucidate the role of PTGDS in skin fibrosis in SSc and evaluate its potential as a therapeutic target. Methods PTGDS expression in skin tissues from SSc patients was analysed through bioinformatics and validated using immunohistochemistry, RT-PCR, and Western blotting. The biological role of PTGDS in fibroblast inflammatory priming was examined using PTGDS-overexpressed BJ cells and the PTGDS inhibitor AT56 in vitro. The therapeutic effect of targeting PTGDS in skin inflammation and fibrosis was validated using a bleomycin (BLM)-induced skin fibrosis mouse model. Results PTGDS expression levels were significantly elevated in the dermal fibroblasts of SSc patients. In vitro, overexpression of PTGDS resulted in the upregulation of various chemokines in skin fibroblasts, subsequently enhancing the migration of CD4+ T cells, particularly the Th2 subset, which was effectively reversed by inhibition of PTGDS with the inhibitor AT56. PTGDS-overexpressed fibroblasts promoted Th2 cell infiltration and skin fibrosis, and oral administration of AT56 significantly attenuated BLM-induced skin inflammation and fibrosis in vivo. Conclusion PTGDS-induced pro-inflammatory fibroblasts caused Th2 cell infiltration and skin fibrosis. Inhibition of PTGDS attenuated the inflammation and fibrosis in the skin. These results demonstrate that PTGDS is a critical regulator of the pro-inflammatory function of skin fibroblasts, providing a promising therapeutic target for SSc.