Abnormal oxysterol metabolism has been observed in the peripheral blood of SLE patients, but its role in systemic lupus erythematosus (SLE) skin lesions remains unclear. Targeted oxidized lipid metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS) was performed to quantify oxysterols in SLE skin lesions. Immunohistochemical staining and single-cell sequencing data analysis confirmed the upregulation of oxysterol-encoding enzymes CH25H and CYP7B1. The impact on fibroblast-mediated PBMCs chemotaxis was assessed using a transwell chamber. We identified aberrant oxidized cholesterol metabolism in SLE skin lesions, characterized by elevated levels of 7-ketocholesterol, 5α-6α-cholestane-3β,5α,6β-triol, and so on. Fibroblasts were the primary cells expressing oxysterol-encoding genes, with CH25H and CYP7B1 expression upregulated via the IL-1β-mediated p38 MAPK and NFκB pathways. Notably, IL-1β-stimulated fibroblasts demonstrated enhanced PBMCs recruitment, which was attenuated by a GPR183 inhibitor. Our findings reveal a potential mechanism by which fibroblasts contribute to immune cell recruitment in SLE skin lesions by expression of CH25H and CYP7B1. This study underscores the significance of oxysterol metabolism in SLE skin lesion pathogenesis and highlights potential therapeutic targets for SLE skin lesion treatment. • SLE skin lesions show abnormal oxysterol metabolism, with fibroblasts being the main source of increased CH25H and CYP7B1 genes. • IL-1β-mediated p38 MAPK and NFκB pathways implicated in CH25H and CYP7B1 upregulation. • Enhanced PBMCs recruitment by IL-1β-stimulated fibroblasts can be attenuated by a GPR183 inhibitor, offering potential SLE skin lesion treatment.

中文翻译：

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氧甾醇有助于 SLE 皮肤病变的免疫细胞募集


已在 SLE 患者的外周血中观察到氧甾醇代谢异常，但其在系统性红斑狼疮 （SLE） 皮肤病变中的作用仍不清楚。使用液相色谱-质谱 （LC-MS） 进行靶向氧化脂质代谢组学分析，以量化 SLE 皮肤病变中的氧甾醇。免疫组织化学染色和单细胞测序数据分析证实了氧甾醇编码酶 CH25H 和 CYP7B1 的上调。使用 transwell 室评估对成纤维细胞介导的 PBMCs 趋化性的影响。我们在 SLE 皮损中发现了异常的氧化胆固醇代谢，其特征是 7-酮胆固醇、 5α-6α-胆甾烷-3β，5α，6β-三醇等水平升高。成纤维细胞是表达氧甾醇编码基因的原代细胞，CH25H 和 CYP7B1 表达通过 IL-1β 介导的 p38 MAPK 和 NFκB 通路上调。值得注意的是，IL-1β 刺激的成纤维细胞表现出增强的 PBMC 募集，GPR183 抑制剂减弱了这种募集。我们的研究结果揭示了成纤维细胞通过表达 CH25H 和 CYP7B1 促进 SLE 皮肤病变免疫细胞募集的潜在机制。本研究强调了氧甾醇代谢在 SLE 皮肤病变发病机制中的重要性，并强调了 SLE 皮肤病变治疗的潜在治疗靶点。• SLE 皮损显示氧甾醇代谢异常，成纤维细胞是 CH25H 和 CYP7B1 基因增加的主要来源。• IL-1β 介导的 p38 MAPK 和 NFκB 通路与 CH25H 和 CYP7B1 上调有关。• GPR183 抑制剂可以减弱 IL-1β 刺激的成纤维细胞增强的 PBMC 募集，从而提供潜在的 SLE 皮肤病变治疗。