Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.
Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa.
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DOI：
10.1136/annrheumdis-2018-213197
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发表时间：
2018-11
影响因子：
27.4
通讯作者：
Kahlenberg JM
中科院分区：
文献类型：
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作者：
Sarkar MK;Hile GA;Tsoi LC;Xing X;Liu J;Liang Y;Berthier CC;Swindell WR;Patrick MT;Shao S;Tsou PS;Uppala R;Beamer MA;Srivastava A;Bielas SL;Harms PW;Getsios S;Elder JT;Voorhees JJ;Gudjonsson JE;Kahlenberg JM
皮肤炎症和光敏性在皮肤（CLE）和系统性红斑狼疮（SLE）患者中很常见，但对调节这些特征的机制知之甚少。在这里，我们研究干扰素κ（IFN-κ）在调节I型IFN和光敏反应中的作用，并检查其在狼疮皮肤中的失调。从CLE病变和健康对照皮肤的微阵列数据分析I型IFN基因的mRNA表达。通过RNA-seq分析培养的原代角质形成细胞、成纤维细胞和内皮细胞中的相似表达。使用CRISPR/Cas9生成IFNK KO角质形成细胞。通过转染细胞的G418选择产生稳定过表达IFN-κ的角质形成细胞。通过STAT 1和STAT 2的磷酸化以及IFN调节基因的qRT-PCR评估IFN应答。通过TUNEL染色分析UVB介导的细胞凋亡。通过正常和CLE损伤皮肤的免疫荧光染色评估体内蛋白表达。IFNK是在病变CLE皮肤中显著增加的两种I型IFN之一（1.5倍变化，FDR q<0.001）。GO分析表明，I型IFN应答在角质形成细胞中富集（FDR=6.8×10−04），而在成纤维细胞和内皮细胞中不富集，这种上皮来源的IFN-κ负责维持健康皮肤中的基线I型IFN应答。IFN-κ水平的增加，如在SLE中所见，放大并加速上皮细胞对IFN-α的反应，并增加角质形成细胞对UV照射的敏感性。值得注意的是，用baricitinib敲除IFN-κ或抑制IFN信号传导消除了UVB诱导的细胞凋亡。总的来说，我们的数据通过促进增强的IFN应答和光敏性将IFN-κ鉴定为CLE病理学中的关键IFN。IFN-κ是UVB预防和CLE导向治疗的潜在新靶点。
Skin inflammation and photosensitivity are common in cutaneous (CLE) and systemic lupus erythematosus (SLE) patients, yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I IFN and photosensitive responses and examine its dysregulation in lupus skin. mRNA expression of type I IFN genes was analyzed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts, and endothelial cells was analyzed via RNA-seq. IFNK KO keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. UVB-mediated apoptosis was analyzed via TUNEL staining. in vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. IFNK is one of two type I IFNs significantly increased (1.5-fold change, FDR q<0.001) in lesional CLE skin. GO analysis showed that type I IFN responses were enriched (FDR=6.8×10−04) in keratinocytes not in fibroblast and endothelial cells and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, knock-out of IFN-κ or inhibition of IFN signaling with baricitinib, abrogates UVB-induced apoptosis. Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.