Journal article
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
eLife, Vol.13, e85914
06/11/2024
DOI: 10.7554/eLife.85914
PMCID: PMC11213570
PMID: 38860651
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.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.
Details
- Title: Subtitle
- The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
- Creators
- Thomas Morgan Li - Hospital for Special SurgeryVictoria ZyulinaEthan S SeltzerMarija DacicYurii Chinenov - Hospital for Special SurgeryAndrea R DaamenKeila R VeigaNoa SchwartzDavid J OliverPamela Cabahug-ZuckermanJose Lora - Hospital for Special SurgeryYong LiuWilliam D ShipmanWilliam G AmblerSarah F TaberKaren B OnelJonathan H Zippin - Weill Cornell MedicineMehdi RashighiJames G KruegerNiroshana AnandasabapathyInez Rogatsky - Cornell UniversityAli Jabbari - University of Iowa, DermatologyCarl P Blobel - Tri-Institutional PhD Program in Chemical BiologyPeter E LipskyTheresa T Lu - Hospital for Special Surgery
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.13, e85914
- DOI
- 10.7554/eLife.85914
- PMID
- 38860651
- PMCID
- PMC11213570
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Language
- English
- Date published
- 06/11/2024
- Academic Unit
- Dermatology
- Record Identifier
- 9984650757802771
Metrics
5 Record Views