The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

作者：Thomas M. Li, Victoria Zyulina, Ethan S Seltzer, Marija Dacic, Yurii Chinenov, Andrea R. Daamen, Keila Veiga, Noa Schwartz, David J. Oliver, Pamela Cabahug‐Zuckerman, José M. Lora, Y. Liu, William Shipman, William G Ambler, Sarah F. Taber, Karen Onel, Jonathan H. Zippin, Mehdi Rashighi, James G. Krueger, Niroshana Anandasabapathy, Inez Rogatsky, Ali Jabbari, Carl Blobel, Peter E. Lipsky, Theresa T. Lu · 发表于：eLife · 年份：2024 · DOI：10.7554/elife.85914 · 被引用次数：15 · 研究领域：Systemic Lupus Erythematosus Research、Immunotherapy and Immune Responses、T-cell and B-cell Immunology

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 pro...