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| Status |
Public on Apr 10, 2023 |
| Title |
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus [array] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
Third-party reanalysis
|
| Summary |
The autoimmune disease lupus erythematosus (lupus) is characterized in part by photosensitivity, where patients can develop inflammatory skin lesions with even ambient ultraviolet radiation (UVR) exposure. Evidence points to a role for type I interferon (IFN-I) in photosensitivity, but mechanistic understanding remains limited. We have shown that photosensitivity in lupus models is at least in part attributable to Langerhans cell (LC) dysfunction. Healthy LCs limit photosensitivity via a disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by releasing soluble epidermal growth factor receptor (EGFR) ligands to support keratinocyte survival. On the other hand, LCs from lesional and even non-lesional lupus model skin show reduced ADAM17 activity and mRNA expression. Non-lesional human lupus skin also showed evidence of LC dysfunction, and, here, we asked how the lupus skin environment contributes to this dysfunction. We show that non-lesional skin in human CLE and multiple photosensitive lupus models share gene expression patterns consistent with a high IFN environment and LC dysfunction. IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) are a mediator of ADAM17 activity, and we show that lupus models have reduced UVR-induced LC ROS generation that is restored by anti-IFNAR1. Our findings suggest shared pathogenic mechanisms of photosensitivity in human and murine lupus skin and a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, predisposing to photosensitivity. Our data also suggest that the beneficial effects of the recently FDA-approved anifrolumab (anti-IFNAR1) on human lupus skin could act in part by restoring LC function.
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| Overall design |
Non-lesional and lesional skin samples were from the same patients.
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| Contributor(s) |
Li TM, Schwartz N, Jabbary A, Oliver D, Chinenov Y, Lu T |
| Citation(s) |
38860651 |
| |
| Submission date |
Mar 14, 2023 |
| Last update date |
Jul 31, 2024 |
| Contact name |
HSS Genomics Research Center |
| Organization name |
Hospital for Special Surgery
|
| Department |
Research
|
| Street address |
535 E 70th St
|
| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10021 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
|
| Samples (14)
|
|
| Relations |
| Reanalysis of |
GSM1267427 |
| Reanalysis of |
GSM1267428 |
| Reanalysis of |
GSM1267429 |
| Reanalysis of |
GSM1267430 |
| Reanalysis of |
GSM1267431 |
| Reanalysis of |
GSM1267432 |
| Reanalysis of |
GSM1267433 |
| Reanalysis of |
GSM1267434 |
| Reanalysis of |
GSM1267435 |
| Reanalysis of |
GSM1267436 |
| BioProject |
PRJNA944662 |
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