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Type I interferon modulates Langerhans cell ADAM17 to promote photosensitivity in lupus

By Thomas M Li, Keila R Veiga, Noa Schwartz, Yurii Chinenov, David J Oliver, Jose Lora, Ali Jabbari, Yong Liu, William D Shipman, Marvin J Sandoval, Isabel F Sollohub, William G Ambler, Mehdi Rashighi, James G. Krueger, Niroshana Anandasabapathy, Carl P Blobel, Theresa T Lu

Posted 18 Aug 2021
bioRxiv DOI: 10.1101/2021.08.18.456792

Type I IFN (IFN-I) mediates autoimmune and inflammatory conditions, and better understanding IFN-I-driven pathogenesis could expand therapeutic possibilities. Lupus is an autoimmune disease characterized by photosensitivity, inflammatory skin lesions, and systemic organ damage. Patients have an IFN-I signature in blood and tissues and anifrolumab (anti-IFNAR1), developed for lupus and recently FDA-approved, underscores the importance of IFN-I in pathogenesis. Anifrolumab is especially efficacious for cutaneous disease, but mechanisms are poorly understood. Langerhans cells (LCs) normally limit UVR-induced skin injury via ADAM17, a metalloprotease that clips from the cell membrane and activates skin-protective EGFR ligands. Downregulation of LC ADAM17 mRNA and activity in lupus models contributes to photosensitivity, and here we link IFN-I pathogenesis with LC dysfunction. We show that murine model and human lupus non-lesional skin have IFN-I signatures and that IFN-I reduces ADAM17 sheddase activity in LCs. Furthermore, anti-IFNAR1 in multiple murine lupus models restores LC ADAM17 function and reduces photosensitivity in an EGFR and LC ADAM17-dependent manner. These results suggest that IFN-I contributes to photosensitivity in lupus by downregulating LC ADAM17 function, providing mechanisms for IFN-I pathogenesis and anifrolumab efficacy and highlighting the importance of LCs as a potential therapeutic target.

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