Background/Purpose: Photosensitivity is a common feature in the autoimmune disease lupus erythematosus (LE) where patients develop inflammatory skin lesions in response to ultraviolet radiation (UVR). In patients with the systemic form of the disease (SLE), photosensitivity can also be associated with serious flares of systemic disease. As current treatments are limited, mechanistic understanding of photosensitivity can lead to better care and quality of life. 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. However, what causes LC dysfunction in the lupus models is not known. Type I interferon (IFN-I) is elevated in SLE non-lesional skin, and anifrolumab (anti-IFNAR) showed efficacy in human cutaneous disease, suggesting a pathogenic role for IFN-I in SLE skin. This led us to assess a role for IFN-I in LC ADAM17 dysfunction.

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 LC ADAM17 activity and expression, flow cytometric-based assays were conducted using human and murine LCs. To evaluate photosensitivity, skin inflammation and cellular infiltrate were measured and characterized using in vivo lupus models.

Results: We show that non-lesional skin from human cutaneous LE and photosensitive MRL/lpr and B6.Sle1yaa mice have 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 inflammatory diseases. We further show that anti-IFNAR1 treatment prior to UVR exposure in lupus models restores LC ADAM17 activity and limits photosensitivity.

Conclusion: Together, our results suggest that LC ADAM17 is dysregulated by the elevated IFN-I associated with disease and IFN-I contributes to LE skin disease, in part, by causing LC dysfunction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-interferon-modulates-langerhans-cell-adam17-in-lupus-to-contribute-to-photosensitivity/