Article Text

Download PDFPDF

201 Type I interferon modulates langerhans cell ADAM17 in lupus to contribute to photosensitivity
  1. Thomas M Li1,
  2. Keila R Veiga1,2,
  3. Noa Schwartz1,3,
  4. Jose Lora4,5,
  5. Ali Jabbari6,
  6. Yong Liu7,
  7. William D Shipman1,8,
  8. Marvin J Sandoval1,9,
  9. Isabel F Sollohub1,
  10. Mehdi Rashighi10,
  11. James G Krueger6,
  12. Niroshana Anandasabapathy7,
  13. David J Oliver11,
  14. Yurii Chinenov11,
  15. Carl P Blobel4,5 and
  16. Theresa T Lu1,2,3,9
  1. 1Autoimmunity and Inflammation Program, HSS Research Institute, New York, NY 10021, USA
  2. 2Pediatric Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, USA
  3. 3Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY USA
  4. 4Arthritis and Tissue Degeneration Program, HSS Research Institute, New York, NY, USA
  5. 5Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
  6. 6Laboratory of Investigative Dermatology, Rockefeller University, New York, NY, USA
  7. 7Department of Dermatology, Weill Cornell Medical College, New York, NY, USA
  8. 8Weill Cornell Tri-Institutional MD-PhD Program, New York, NY, USA
  9. 9Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
  10. 10Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, USA
  11. 11David Z. Rosensweig Genomics Research Center, HSS Research Institute, New York, NY, USA


Background Photosensitivity is a common feature in systemic lupus erythematosus (SLE), is considered to be a major contributor to SLE skin disease, and can be associated with serious flares of systemic disease, but mechanistic understanding remains limited. Several lines of evidence including the finding of a type I interferon (IFN-I) signature in non-lesional skin, the potentiation of keratinocyte apoptosis by IFN-I, the importance of IFNAR in murine lupus model skin lesion development, and the improved skin scores in the clinical trials of anifrolumab (anti-IFNAR1) point to a pathogenic role for IFN-I in SLE skin disease. We recently showed that Langerhans cells (LCs) limit UVR-induced keratinocyte apoptosis and skin injury via ADAM17-mediated EGFR ligand activation and that reduced LC ADAM17 activity in two lupus models contributed to their photosensitivity. Non-lesional human SLE skin also showed evidence of a dysfunctional LC-keratinocyte axis; however, what causes LC dysfunction is not known. Here we test the hypothesis that IFN-I in the skin contributes to LC ADAM17 dysfunction and thus photosensitivity.

Methods To assess IFN-I gene signature, microarray of non-lesional skin from human cutaneous LE and RNA sequencing of whole skin from lupus mouse models were performed. To quantify human and murine LC ADAM17 activity and expression, in vitro and ex vivo flow cytometric-based assays were conducted LCs. To assay photosensitivity, readouts of skin inflammation and cellular infiltrate were measured and characterized.

Results We show that non-lesional skin from human cutaneous LE and photosensitive MRL/lpr and B6.Sle1yaa mice all share IFN-I signatures and that IFN-I is sufficient to reduce human and murine LC ADAM17 activity independently of surface ADAM17 levels. IFN-I induced LC ADAM17 activity defects were abrogated with tofaticinib, a JAK kinase inhibitor approved for rheumatoid arthritis and other rheumatologic diseases. We further show that anti-IFNAR1 treatment prior to UVR exposure in lupus models restores LC ADAM17 activity and limits photosensitivity.

Conclusions Together, our results suggest a model whereby the elevated IFN-I in non-lesional skin contributes to photosensitivity at least in part by causing LC ADAM17 dysfunction. The corollary is that anti-IFNAR has beneficial effects at least in part by correcting LC ADAM17 dysfunction.

Acknowledgements This work was supported by National Institutes of Health R01AI079178 (TTL), the Lupus Research Alliance (TTL), the St. Giles Foundation (TTL) and AΩA Carolyn L. Kuckein Student Research Fellowship (TML).

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:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.