The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

eLife, Journal Year: 2024, Volume and Issue: 13

Published: June 11, 2024

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 metalloprotease 17 (ADAM17)-mediated release epidermal growth factor receptor (EGFR) ligands LC ADAM17 sheddase activity reduced in lupus. Here, we sought understand how the environment contributes dysfunction and, process, differentiate between effects on function, expression, numbers. show through transcriptomic analysis shared IFN-rich non-lesional across human three murine models: MRL/lpr, B6.Sle1yaa, imiquimod (IMQ) mice. IFN-I inhibits LCs, IFNAR blockade model mice restores activity, all without consistent protein expression or Anti-IFNAR-mediated function restoration associated with photosensitive responses are dependent EGFR signaling ADAM17. Reactive oxygen species (ROS) known mediator activity; UVR-induced ROS production mice, restored anti-IFNAR, cytoplasmic origin. Our findings suggest promotes at least part inhibiting raise possibility anifrolumab ameliorates restoring this function. This work provides insight into IFN-I-mediated mechanisms, regulation, potential mechanism action for

Language: Английский

Depression-like behavior is associated with changes in the meningeal lymphatic vasculature and meningeal B cells in a murine lupus model

Journal of Leukocyte Biology, Journal Year: 2025, Volume and Issue: 117(4)

Published: April 1, 2025

Abstract Meningeal lymphatic vasculature (mLV) comprises a network of vessels responsible for draining immune cells and fluid from the central nervous system (CNS) into deep cervical lymph nodes. While changes in mLV function have been implicated several neurodegenerative disorders, its role autoimmune diseases is less clear. Systemic lupus erythematosus (SLE) an disease affecting multiple organs. When SLE affects CNS, it known as neuropsychiatric (NPSLE), although status during NPSLE has not yet evaluated. Here, by using FcγRIIb−/− murine model, we found that this model develops along with increased coverage at 4 mo age. Altered B cell developmental stages were evident mouse model. In fact, clusters meninges mice also observed. These findings suggest morphology are together meningeal population could impact on symptoms.

Language: Английский

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Aug. 18, 2021

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 skin support a pathogenic role for IFN-I, but mechanistic understanding limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via disintegrin and metalloprotease 17 (ADAM17) release epidermal growth factor receptor (EGFR) ligands limit UVR-induced keratinocyte apoptosis However, LC ADAM17 activity reduced in non-lesional model skin, data point LC-mediated protection human lupus. Here, we asked about the IFN-rich environment implications this regulation Methods Gene expression patterns from multiple murine models were examined. used MRL/lpr, B6.Sle1yaa, imiquimod vivo studies assess IFN-I Results show shared across systems, inhibits activity, anti-IFNAR restores function reduces photosensitivity EGFR ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ROS restored anti-IFNAR. Conclusions Our findings suggest promotes causing ameliorates at least part restoring function. This work provides insight into IFN-I-mediated mechanisms, regulation, mechanism action

Language: Английский