Background: Immune dysregulation plays a crucial role in the pathogenesis of systemic sclerosis (SSc)[1]. Lipocalin-type prostaglandin D synthase (PTGDS), which participates in immune regulation through the synthesis of prostaglandin D2 (PGD2), is associated with autoimmunity and fibrosis[2]. However, the expression, mechanism of action, and pathogenic role of PTGDS in SSc remain unclear.

Objectives: This study aims to explore the role and potential mechanisms of PTGDS in SSc.

Methods: The expression of PTGDS in the skin tissues and dermal fibroblasts of SSc patients was analyzed based on GEO data and confirmed through immunohistochemistry, qPCR, and western blotting. The role of PTGDS in inflammation and fibrosis was investigated using a PTGDS-overexpression vector and inhibitor (AT56) in dermal fibroblasts. The pathogenic role of PTGDS in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse model of skin inflammation and fibrosis.

Results: PTGDS levels were significantly elevated in the skin tissues and dermal fibroblasts of SSc patients, correlating with the severity of skin fibrosis. In vitro studies, overexpression of PTGDS upregulated CCL2, IL-6, IL32, CCL8, CCL13, and CCL19 in dermal fibroblasts. Mechanistically, PTGDS induced senescence of dermal fibroblasts in a P53-P21 pathway-dependent manner, leading to increased secretion of cytokines, chemotaxis of macrophage infiltration and differentiation, activation of surrounding fibroblasts, and enhanced ECM deposition. Oral administration of the inhibitor AT56 significantly reduced BLM-induced skin inflammation and fibrosis in vivo.

Conclusion: PTGDS could be a promising therapeutic target for improving treatment strategies for skin inflammation and fibrosis in SSc.

[1] Fang, D., et al., Immune cell dysregulation as a mediator of fibrosis in systemic sclerosis. Nat Rev Rheumatol, 2022. 18 (12): p. 683-693.

[2] Ito, H., et al., PGD2-CRTH2 pathway promotes tubulointerstitial fibrosis. J Am Soc Nephrol, 2012. 23 (11): p. 1797-809.

REFERENCES Acknowledgements: NIL.

Disclosure of Interests: None declared.