Background Photosensitivity is a common feature in systemic lupus erythematosus (SLE), is considered to be a major contributor to SLE skin disease, and can be associated with serious flares of systemic disease, but mechanistic understanding remains limited. Several lines of evidence including the finding of a type I interferon (IFN-I) signature in non-lesional skin, the potentiation of keratinocyte apoptosis by IFN-I, the importance of IFNAR in murine lupus model skin lesion development, and the improved skin scores in the clinical trials of anifrolumab (anti-IFNAR1) point to a pathogenic role for IFN-I in SLE skin disease. We recently showed that Langerhans cells (LCs) limit UVR-induced keratinocyte apoptosis and skin injury via ADAM17-mediated EGFR ligand activation and that reduced LC ADAM17 activity in two lupus models contributed to their photosensitivity. Non-lesional human SLE skin also showed evidence of a dysfunctional LC-keratinocyte axis; however, what causes LC dysfunction is not known. Here we test the hypothesis that IFN-I in the skin contributes to LC ADAM17 dysfunction and thus photosensitivity.
Methods To assess IFN-I gene signature, microarray of non-lesional skin from human cutaneous LE and RNA sequencing of whole skin from lupus mouse models were performed. To quantify human and murine LC ADAM17 activity and expression, in vitro and ex vivo flow cytometric-based assays were conducted LCs. To assay photosensitivity, readouts of skin inflammation and cellular infiltrate were measured and characterized.
Results We show that non-lesional skin from human cutaneous LE and photosensitive MRL/lpr and B6.Sle1yaa mice all share IFN-I signatures and that IFN-I is sufficient to reduce human and murine LC ADAM17 activity independently of surface ADAM17 levels. IFN-I induced LC ADAM17 activity defects were abrogated with tofaticinib, a JAK kinase inhibitor approved for rheumatoid arthritis and other rheumatologic diseases. We further show that anti-IFNAR1 treatment prior to UVR exposure in lupus models restores LC ADAM17 activity and limits photosensitivity.
Conclusions Together, our results suggest a model whereby the elevated IFN-I in non-lesional skin contributes to photosensitivity at least in part by causing LC ADAM17 dysfunction. The corollary is that anti-IFNAR has beneficial effects at least in part by correcting LC ADAM17 dysfunction.
Acknowledgements This work was supported by National Institutes of Health R01AI079178 (TTL), the Lupus Research Alliance (TTL), the St. Giles Foundation (TTL) and AΩA Carolyn L. Kuckein Student Research Fellowship (TML).
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