Photosensitivity, a sensitivity to ultraviolet radiation, is a hallmark symptom of systemic and cutaneous lupus erythematosus (SLE and CLE). We have previously shown that photosensitivity in SLE models is caused by reduced function of Langerhans cells (LC) disintegrin and metalloprotease 17 (ADAM17), a sheddase that normally limits UVR-induced skin inflammation by activating epidermal growth factor receptor (EGFR) ligands. We also showed that LC ADAM17 activity is reduced in murine models and human SLE and that this LC ADAM17 dysfunction contributed to photosensitivity. The aim of this study is to understand why lupus LCs are dysfunctional and how type I interferon (IFN-I) in lupus skin contributes to LC ADAM17 dysregulation.

In this study we utilize multiple photosensitive SLE models and skin obtained from healthy human volunteers. LC ADAM17 activity and expression was measured by flow cytometry.

We found IFN-I signatures in non-lesional skin of MRL/lpr and B6.Sle1yaa photosensitive SLE models in addition to that of CLE patients, suggesting the similarities in gene expression patterns between human and mouse lupus skin. We also showed that IFN-I inhibits murine and human LC ADAM17 activity, and anti-IFNAR1 in SLE models restores LC ADAM17 function and reduces photosensitivity in EGFR− and LC ADAM17-dependent manners.

Together our findings suggest a model whereby the IFN-I-rich microenvironment in non-lesional lupus skin inhibits UVR-induced ADAM17 activity, leading to photosensitivity. These results suggest that the beneficial effects of the recently FDA-approved anifrolumab on human lupus skin may be attributable to effects on improving LC ADAM17 activity.

This content is only available via PDF.