Abstract:
The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.
摘要:
自身免疫性疾病红斑狼疮(狼疮)的特征是光敏性,即使是环境紫外线辐射(UVR)暴露也可能导致炎症性皮肤病变的发展。我们先前已经表明,朗格汉斯细胞(LC)通过整合素和金属蛋白酶17(ADAM17)介导的表皮生长因子受体(EGFR)配体的释放限制了角质形成细胞的凋亡和光敏性,并且狼疮中LCADAM17脱落酶活性降低。这里,我们试图了解狼疮皮肤环境如何导致LCADAM17功能障碍,在这个过程中,区分对LCADAM17脱落酶功能的影响,LCADAM17表达,LC号码。我们通过转录组学分析显示,在人类狼疮和三种鼠模型的非皮损皮肤中共享富含IFN的环境:MRL/lpr,B6.Sle1yaa,和咪喹莫特(IMQ)小鼠。IFN-I抑制小鼠和人LC中的LCADAM17脱落酶活性,和IFNAR阻断狼疮模型小鼠恢复LCADAM17脱落酶活性,均对LCADAM17蛋白表达或LC数量无一致影响。抗IFNAR介导的LCADAM17脱落酶功能恢复与依赖于EGFR信号传导和LCADAM17的光敏反应降低相关。活性氧(ROS)是ADAM17活性的已知介质;我们显示UVR诱导的LCROS产生在狼疮模型小鼠中减少,通过反IFNAR恢复,起源于细胞质。我们的发现表明,IFN-I至少部分地通过抑制UVR诱导的LCADAM17脱落酶功能来促进光敏性,并部分地通过恢复该功能来提高anifroummab改善狼疮皮肤病的可能性。这项工作提供了深入了解IFN-I介导的疾病机制,LC规定,以及阿尼福鲁单抗在狼疮中的潜在作用机制。