{"doi":"10.1101/2021.08.18.456792","title":"The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus","abstract":"ABSTRACT Background The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon α/breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity. Methods Gene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity. Results We show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR. Conclusions Our findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217767,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":815037,"name":"Victoria Zyulina","orcid":"0000-0001-7329-8045","position":1,"is_corresponding":false},{"id":815038,"name":"Ethan S Seltzer","orcid":"0000-0001-9675-9609","position":2,"is_corresponding":false},{"id":815669,"name":"Marija Dacic","orcid":null,"position":3,"is_corresponding":false},{"id":334718,"name":"Yurii Chinenov","orcid":"0000-0001-5226-8541","position":4,"is_corresponding":false},{"id":815039,"name":"Andrea R. Daamen","orcid":"0000-0002-0301-2811","position":5,"is_corresponding":false},{"id":815670,"name":"Keila Veiga","orcid":null,"position":6,"is_corresponding":false},{"id":709151,"name":"Noa Schwartz","orcid":"0000-0002-5577-3196","position":7,"is_corresponding":false},{"id":384369,"name":"David J. Oliver","orcid":null,"position":8,"is_corresponding":false},{"id":747316,"name":"José M. Lora","orcid":"0000-0002-6654-0929","position":9,"is_corresponding":false},{"id":454548,"name":"Ali Jabbari","orcid":"0000-0002-8559-7314","position":10,"is_corresponding":false},{"id":815040,"name":"Yong Liu","orcid":"0000-0001-7395-4153","position":11,"is_corresponding":false},{"id":356361,"name":"William Shipman","orcid":"0000-0002-7911-0610","position":12,"is_corresponding":false},{"id":732252,"name":"William G Ambler","orcid":"0000-0003-0573-9173","position":13,"is_corresponding":false},{"id":815671,"name":"Sarah F. Taber","orcid":null,"position":14,"is_corresponding":false},{"id":320032,"name":"Karen Onel","orcid":"0000-0002-1238-5361","position":15,"is_corresponding":false},{"id":281690,"name":"Jonathan H. Zippin","orcid":"0000-0002-5882-0189","position":16,"is_corresponding":false},{"id":466272,"name":"Mehdi Rashighi","orcid":"0000-0002-9170-5887","position":17,"is_corresponding":false},{"id":18939,"name":"James G. Krueger","orcid":"0000-0002-3775-1778","position":18,"is_corresponding":false},{"id":18942,"name":"Niroshana Anandasabapathy","orcid":"0000-0002-0473-8358","position":19,"is_corresponding":false},{"id":334719,"name":"Inez Rogatsky","orcid":"0000-0003-3514-5077","position":20,"is_corresponding":false},{"id":361885,"name":"Carl Blobel","orcid":"0000-0001-5053-3137","position":21,"is_corresponding":false},{"id":310749,"name":"Peter E. Lipsky","orcid":"0000-0002-9287-1676","position":22,"is_corresponding":false},{"id":329627,"name":"Theresa T. Lu","orcid":"0000-0002-5707-8744","position":23,"is_corresponding":false},{"id":329621,"name":"Thomas M. Li","orcid":"0000-0003-3503-3593","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T23:53:24.683898Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}