Cutaneous lupus erythematosus (CLE) rashes are disfiguring and often refractory to usual lupus therapies. A prominent and pathogenic feature of CLE is robust upregulation of type I interferon (IFN)-regulated genes, yet the drivers of this signature are poorly understood in the skin. Using microarray analysis of 90 CLE lesions, we confirmed a prominent type I IFN signature for both discoid and subacute cutaneous lupus characterized by a transcriptional network surrounding STAT1 overexpression. To determine which type I IFNs were driving this IFN signature, we analyzed expression of all type I IFN genes in CLE lesional and control skin. Only two type I IFN transcripts were upregulated in CLE: IFNα10, presumably produced by plasmacytoid dendritic cells recruited to the dermis, and IFNκ, a keratinocyte-produced type I IFN. Immunofluorescence identified IFNκ as robustly produced in CLE epithelium compared to control skin. Both IFNα and IFNκ induced expression of IFN signature genes (MX1, OAS1, IRF7) in control and CLE keratinocytes. However, evaluation of genome-wide response to type I IFNs via RNA sequencing identified a distinct population of transcripts that were highly upregulated in CLE vs. control keratinocytes. Comparison of this unique mRNA population with CLE lesional microarray data identified the majority of CLE-IFN-skewed keratinocyte genes as also altered in CLE lesions. These data support a role for the epidermis in both production of and abnormal response to type I IFNs in CLE and provide a mechanism for the promising effects of type I IFN receptor blockade for CLE.
Assistant Professor of Internal Medicine
University of Michigan