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

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.

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© 2024, Li et al.

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TL, VZ, ES, MD, YC, KV, DO, PC, YL, WS, ST, KO, MR, IR The other authors declare that no competing interests exist. AD Andrea R Daamen, is an employee of AMPEL BioSolutions, but has no financial conflicts of interest to report.. NS Noa Schwartz, was awarded the Lupus Therapeutics: The Clinical Trial Network Infrastructure Grant, received by The Albert Einstein College of Medicine. The author received payment for lectures at the Congress of Clinical Rheumatology East and the Congress of Clinical Rheumatology West. The author has no other competing interests to declare.. JL Jose Lora, has received the grants F31 NIH GM136144 and T32 NIH GM008539. The author has received stock or stock options from NASDAQ/NYSE Ticker: FULC, ABCL, AVXL, VOR, MRNA, BNTX, SAVA, OCGN, CTMX, BCEL, GE. The author has no other competing interests to declare.. WA William G Ambler, received support for travel and attending Lupus 21st century meeting in 2021. The author has no other competing interests to declare.. JZ Jonathan H Zippin, received a grant from NIH NIAMS, and consulting fees from Hoth Therapeutics and Pfizer. The author received payment for participation on a Data Safety Monitoring Board/ Advisory Board for Hoth Therapeutics and acts as President elect for PASPCR. The author holds stock options from Hoth Therapeutics, FoxWayne Inc and YouV labs. The author has no other competing interests to declare.. JK James G Krueger, has received grant support from AbbVie, Akros, Allergan, Amgen, Avillion, Biogen, Botanix, Boehringer Ingelheim, Bristol-Myers Squibb, Exicure, Innovaderm, Incyte, Janssen, Kyowa Kirin, Lilly, Nimbus Lackshmi, Novan, Novartis, PAREXEL, Pfizer, Regeneron, UCB, Vitae Pharmaceuticals. The author received consulting fees from AbbVie, Aclaris, Allergan, Almirall, Amgen, Artax Biopharma, Arena, Aristea, Asana, Aurigene, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Escalier, Galapagos, Janssen, Kyowa Kirin, Lilly, MoonLake Immunotherapeutics, Nimbus, Novartis, Pfizer, Sanofi, Sienna Biopharmaceuticals, Sun Pharma, Target-Derm, UCB, Valeant, Ventyx. The author has no other competing interests to declare.. NA Niroshana Anandasabapathy, has received the following grants: NIAMS AR080436-01, NIAMS R56AR078686-01 and NIH NIAMS 5R01 GRANT AR070234-05. The author received consulting fees from Immunitas, Shennon Bio and Janssen. The author received payment as a lecturer from 23 and me, Cellino and Bristol Meyer Squibb Genomics. They are also a board member of the Society of Investigative Dermatology. The author has no other competing interests to declare.. AJ Ali Jabbari, has received grants from the NIH and the VA and consulting fees from Pfizer. The author has no other competing interests to declare.. CB Carl P Blobel, The patent number is US10024844B2 and the title of the patent is Identification of an inhibitor of iRhom1 or an inhibitor of iRhom2". PL Peter E Lipsky, is an employee of AMPEL BioSolutions, but has no financial conflicts of interest to report.. TL Theresa T Lu, has received the following grants: NIH R01AI079178, NIH R21 AR081493, Department of Defense W81XWH-21-LRP-IPA, Lupus Research Alliance Lupus Innovation Award grant, Barbara Volcker Center for Women and Rheumatic Diseases grant. She has also received funding support from the St. Giles Foundation and A Lasting Mark Foundation. She has received consulting fees from Pfizer, and has a received payment from Bristol Meyers Squibb for giving a lecture. The author has received payment for attending Lupus 21st Century meeting. The author has no other competing interests to declare..