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Series GSE222573 Query DataSets for GSE222573
Status Public on Jan 10, 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
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.
 
Overall design Comparative gene expression profiling analysis of RNA-seq data from non-lesional ears of MRL/+ vs MRL/lpr mice and B6 vs B6.Sle1yaa mice.
 
Contributor(s) Li TM, Schwartz N, Chinenov Y, Daamen AR, Oliver DJ, Lu TT
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Submission date Jan 10, 2023
Last update date Jan 10, 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 (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (37)
GSM6926608 non-lesional ear skin from B6 control mice [B6-1_S9_L001]
GSM6926609 non-lesional ear skin from B6 control mice [B6-1_S9_L002]
GSM6926610 non-lesional ear skin from B6 control mice [B6-2_S10_L001]
Relations
BioProject PRJNA922549

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE222573_countMatrix_B6_Sle1.tsv.gz 993.2 Kb (ftp)(http) TSV
GSE222573_countMatrix_lpr_vs_mrl.tsv.gz 913.8 Kb (ftp)(http) TSV
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Raw data are available in SRA
Processed data are available on Series record
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