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Cutaneous Lupus & Photosensitivity
404 The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
  1. Thomas M Li1,†,§,
  2. Pamela Zuckerman1,§,
  3. Victoria Zyulina1,2,§,
  4. Ethan S Seltzer1,‡,§,
  5. Marija Dacic3,4,5,
  6. Yurii Chinenov3,
  7. Andrea R Daamen6,
  8. Keila R Veiga1,7,8,††,
  9. Noa Schwartz1,9,‡‡,
  10. David J Oliver3,
  11. Jose Lora4,5,
  12. Ali Jabbari10,§§,
  13. Yong Liu11,
  14. William D Shipman1,12,13,,
  15. William G Ambler1,7,8,
  16. Sarah F Taber7,8,
  17. Karen B Onel7,8,
  18. Jonathan H Zippin11,
  19. Mehdi Rashighi14,
  20. James G Krueger10,
  21. Niroshana Anandasabapathy11,12,13,
  22. Inez Rogatsky2,3,4,13,
  23. Carl P Blobel4,5,15,
  24. Peter E Lipsky6 and
  25. Theresa T Lu1,2,7,8,13
  1. 1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, NY, USA
  2. 2Department of Microbiology and Immunology, Weill Cornell Medical College; New York, NY, USA
  3. 3David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery Research Institute; New York, NY, USA
  4. 4Arthritis and Tissue Degeneration Program, Hospital for Special Surgery Research Institute, New York, USA
  5. 5Physiology, Biophysics, and Systems Biology Program, Weill Cornell Graduate School of Medical Sciences; New York, NY, USA
  6. 6AMPEL BioSolutions, Charlottesville, VA, USA
  7. 7Pediatric Rheumatology, Department of Medicine, Hospital for Special Surgery; New York, NY, USA
  8. 8Department of Pediatrics, Weill Cornell Medical College; New York, USA
  9. 9Rheumatology, Department of Medicine, Hospital for Special Surgery; New York, NY, USA
  10. 10Laboratory of Investigative Dermatology, Rockefeller University, New York, NY, USA
  11. 11Department of Dermatology, Weill Cornell Medical College; New York, NY, USA
  12. 12Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, Weill Cornell Medical College; New York, NY, USA
  13. 13Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences; New York, NY, USA
  14. 14Department of Dermatology, University of Massachusetts Medical School; Worcester, USA
  15. 15Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medical College; New York, NY, USA
  16. §These authors share first authorship
  17. †Current address Icahn School of Medicine at Mount Sinai; New York, USA
  18. ‡Current address Graduate Program in Bioscience, Rockefeller University; New York, USA

Abstract

Background The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon α/βreceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I , but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC- mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity.

Methods Gene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity.

Results We show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17- dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR.

Conclusions Our findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/lupus-2023-lupus21century.27

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