Gehlhausen Jeff R, Kong Yong, Baker Emily, Ramachandran Sarika, Koumpouras Fotios, Ko Christine J, Vesely Matthew, Little Alicia J, Damsky William, King Brett, Iwasaki Akiko
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
School of Public Health, New Haven, Connecticut, USA.
J Invest Dermatol. 2025 May 21. doi: 10.1016/j.jid.2025.04.033.
Cutaneous lupus is an inflammatory skin disease causing highly morbid inflamed skin and hair loss. To investigate the pathophysiology of cutaneous lupus, we performed single-cell RNA and spatial sequencing of lesional and nonlesional cutaneous lupus skin compared with that of healthy controls. Pathway enrichment analyses of lesional keratinocytes revealed elevated responses to IFN-I, IFN-II, TNF, and apoptotic signaling. Detailed clustering demonstrated unique fibroblasts specific to lupus skin with likely roles in inflammatory cell recruitment and fibrosis. We also evaluated the association of retroelement expression with IFN-I in the skin. We observed increased retroelement expression that correlated with IFN-stimulated genes across multiple cell types. Moreover, we saw elevated expression of genes involved in RIG-I and cGAS-STING pathways, which transduce elevated nucleic acid signals. Treatment of active cutaneous lupus with anifrolumab reduced RIG-I and cGAS-STING pathways in addition to the most abundant retroelement family, L2b. Our studies better define IFN-I IFN-mediated immunopathology in cutaneous lupus and identify an association between retroelement expression and IFN signatures in cutaneous lupus.
皮肤性狼疮是一种炎症性皮肤病，可导致皮肤高度病态发炎和脱发。为了研究皮肤性狼疮的病理生理学，我们对病变和非病变的皮肤性狼疮皮肤进行了单细胞RNA和空间测序，并与健康对照进行了比较。对病变角质形成细胞的通路富集分析显示，对I型干扰素、II型干扰素、肿瘤坏死因子和凋亡信号的反应增强。详细的聚类分析表明，狼疮皮肤有独特的成纤维细胞，可能在炎症细胞招募和纤维化中起作用。我们还评估了逆转录元件表达与皮肤中I型干扰素的关联。我们观察到逆转录元件表达增加，且在多种细胞类型中与干扰素刺激基因相关。此外，我们还发现参与维甲酸诱导基因I（RIG-I）和环鸟苷酸-腺苷酸合成酶-干扰素基因刺激因子（cGAS-STING）通路的基因表达升高，这些通路可转导升高的核酸信号。用阿尼鲁单抗治疗活动性皮肤性狼疮，除了最丰富逆转录元件家族L2b外，还可降低RIG-I和cGAS-STING通路。我们的研究更好地定义了皮肤性狼疮中I型干扰素介导的免疫病理学，并确定了皮肤性狼疮中逆转录元件表达与干扰素特征之间的关联。
