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