The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
- Hospital for Special Surgery, United States
- Weill Cornell Medicine, United States
- Ampel BioSolutions, United States
- University of Massachusetts Medical School, United States
- Rockefeller University, United States
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.
Data availability
The murine RNAseq data have been deposited in GEO (GSE222573for MRL/lpr and B6.Sle1yaa mice; GSE255519 for IMQ mice). Non-lesional human DLE microarray data were deposited with accession number GSE227329 with reanalysis of healthy control samples from GSE52471. All other data supporting the findings of this study are available within the paper and its Supplementary Materials.
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The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupusNCBI Gene Expression Omnibus, GSE222573.
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The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupusNCBI Gene Expression Omnibus, GSE255519.
Article and author information
Author details
Funding
Alpha Omega Alpha Honor Medical Society Carolyn L. Kuckein fellowship
- Thomas Morgan Li
NIH (R01AR077194)
- Ali Jabbari
NIH (DK099087)
- Inez Rogatsky
NIH (R35GM134907)
- Carl P Blobel
NIH (R01AI079178)
- Theresa T Lu
NIH (R21 AR081493)
- Theresa T Lu
DOD (W81XWH-21-LRP-IPA)
- Theresa T Lu
Lupus Research Alliance
- Theresa T Lu
St. Giles Foundation
- Theresa T Lu
Barbara Volcker Center for Women and Rheumatic Diseases
- Theresa T Lu
A Lasting Mark Foundation
- Theresa T Lu
HSS Medical Student Summer Research Fellowhship
- Thomas Morgan Li
Erwin Schrodinger Fellowship (J 4638-B FWF)
- Victoria Zyulina
NIH (T32AR071302)
- Noa Schwartz
- William D Shipman III
NIH MSTP grant (T32GM007739)
- William D Shipman III
Tow Foundation
- Yurii Chinenov
- David J Oliver
NIH (K08 AR069111)
- Ali Jabbari
Veterans Administration VA Merit (I01 BX004907)
- Ali Jabbari
Dermatology Foundation Physician Scientist Career Development Award
- Ali Jabbari
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Detlef Weigel, Max Planck Institute for Biology Tübingen, Germany
Ethics
Animal experimentation: All animal procedures were performed in accordance with the regulations of the Institutional Animal Care and Use Committee at Weill Cornell Medicine (New York, NY) (Protocol number 2015-0067).
Human subjects: For samples used in microarray analysis --human tissue collection and research use adhered to protocols approved by the Institutional Review and Privacy Boards at the Rockefeller University (IRB# AJA-00740) and New York University (IRB# 10-02117), where participants signed written informed consents. For samples used in suction blistering -- human tissue collection and research use adhered to protocols approved by the Institutional Review and Privacy Board at the Hospital for Special Surgery (IRB# 2019-1998), where participants signed written informed consents.
Version history
- Received: January 2, 2023
- Accepted: June 10, 2024
- Accepted Manuscript published: June 11, 2024 (version 1)
Copyright
© 2024, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
eLife 13:e85914.
https://doi.org/10.7554/eLife.85914
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