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

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Thomas Morgan Li

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3503-3593
  2. Victoria Zyulina

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  3. Ethan S Seltzer

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9675-9609
  4. Marija Dacic

    Physiology, Biophysics, and Systems Biology Program, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
  5. Yurii Chinenov

    David Z Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  6. Andrea R Daamen

    Ampel BioSolutions, Charlottesville, United States
    Competing interests
    Andrea R Daamen, is an employee of AMPEL BioSolutions, but has no financial conflicts of interest to report..
  7. Keila R Veiga

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  8. Noa Schwartz

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5577-3196
  9. David J Oliver

    David Z Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  10. Pamela Cabahug-Zuckerman

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  11. Jose Lora

    Physiology, Biophysics, and Systems Biology Program, Weill Cornell Medicine, New York, United States
    Competing interests
    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..
  12. Yong Liu

    Department of Dermatology, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0196-3285
  13. William D Shipman III

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  14. William G Ambler

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    Competing interests
    William G Ambler, received support for travel and attending Lupus 21st century meeting in 2021. The author has no other competing interests to declare..
  15. Sarah F Taber

    Department of Medicine, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  16. Karen B Onel

    Department of Medicine, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
  17. Jonathan H Zippin

    Department of Dermatology, Weill Cornell Medicine, New York, United States
    Competing interests
    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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5882-0189
  18. Mehdi Rashighi

    Department of Dermatology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  19. James G Krueger

    Laboratory of Investigative Dermatology, Rockefeller University, New York, United States
    Competing interests
    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..
  20. Niroshana Anandasabapathy

    Department of Dermatology, Weill Cornell Medicine, New York, United States
    Competing interests
    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..
  21. Inez Rogatsky

    David Z Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3514-5077
  22. Ali Jabbari

    Laboratory of Investigative Dermatology, Rockefeller University, New York, United States
    Competing interests
    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..
  23. Carl P Blobel

    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, United States
    Competing interests
    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".
  24. Peter E Lipsky

    Ampel BioSolutions, Charlottesville, United States
    Competing interests
    Peter E Lipsky, is an employee of AMPEL BioSolutions, but has no financial conflicts of interest to report..
  25. Theresa T Lu

    Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, United States
    For correspondence
    lut@hss.edu
    Competing interests
    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..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5707-8744

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

  1. 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

  1. Received: January 2, 2023
  2. Accepted: June 10, 2024
  3. 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.

Metrics

  • 135
    views
  • 37
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Thomas Morgan Li
  2. Victoria Zyulina
  3. Ethan S Seltzer
  4. Marija Dacic
  5. Yurii Chinenov
  6. Andrea R Daamen
  7. Keila R Veiga
  8. Noa Schwartz
  9. David J Oliver
  10. Pamela Cabahug-Zuckerman
  11. Jose Lora
  12. Yong Liu
  13. William D Shipman III
  14. William G Ambler
  15. Sarah F Taber
  16. Karen B Onel
  17. Jonathan H Zippin
  18. Mehdi Rashighi
  19. James G Krueger
  20. Niroshana Anandasabapathy
  21. Inez Rogatsky
  22. Ali Jabbari
  23. Carl P Blobel
  24. Peter E Lipsky
  25. Theresa T Lu
(2024)
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
eLife 13:e85914.
https://doi.org/10.7554/eLife.85914

Share this article

https://doi.org/10.7554/eLife.85914

Further reading

    1. Immunology and Inflammation
    Steven Klupt, Kyong Tkhe Fam ... Howard C Hang
    Research Article

    Enterococcus faecium is a microbiota species in humans that can modulate host immunity (Griffin and Hang, 2022), but has also acquired antibiotic resistance and is a major cause of hospital-associated infections (Van Tyne and Gilmore, 2014). Notably, diverse strains of E. faecium produce SagA, a highly conserved peptidoglycan hydrolase that is sufficient to promote intestinal immunity (Rangan et al., 2016; Pedicord et al., 2016; Kim et al., 2019) and immune checkpoint inhibitor antitumor activity (Griffin et al., 2021). However, the functions of SagA in E. faecium were unknown. Here, we report that deletion of sagA impaired E. faecium growth and resulted in bulged and clustered enterococci due to defective peptidoglycan cleavage and cell separation. Moreover, ΔsagA showed increased antibiotic sensitivity, yielded lower levels of active muropeptides, displayed reduced activation of the peptidoglycan pattern-recognition receptor NOD2, and failed to promote cancer immunotherapy. Importantly, the plasmid-based expression of SagA, but not its catalytically inactive mutant, restored ΔsagA growth, production of active muropeptides, and NOD2 activation. SagA is, therefore, essential for E. faecium growth, stress resistance, and activation of host immunity.

    1. Immunology and Inflammation
    Yi-Hong Li, Yi-Sen Yang ... Liquan Huang
    Research Article

    Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit Gγ13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the Gγ13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.