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| Status |
Public on Feb 23, 2024 |
| Title |
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| 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 |
Comparative gene expression profiling analysis of RNA-seq data for
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| Contributor(s) |
Li TM, Schwartz N, Chinenov Y, Daamen AR, Oliver DJ, Dacic M, Jabbari A, Rogatsky I, Lu TT |
| Citation(s) |
38860651 |
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| Submission date |
Feb 09, 2024 |
| Last update date |
Jul 31, 2024 |
| Contact name |
Yurii Chinenov |
| Organization name |
Hospital for special surgery
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| Department |
Research Division
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| Lab |
HSS Genomics Center
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| Street address |
535 E 71 str, Hospital for Special Surgery
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| City |
New york |
| State/province |
New York |
| ZIP/Postal code |
11361 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (19)
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| Relations |
| BioProject |
PRJNA1075143 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE255519_edgeR_DEGs_MD-14749_TL_15499_batch_2024-01-22.xlsx |
13.0 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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