Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which 70% 
of patients experience disfiguring skin inflammation (grouped under the rubric 
of cutaneous lupus erythematosus [CLE]). There are limited treatment options for 
SLE and no Food and Drug Administration-approved therapies for CLE. Studies have 
revealed that IFNs are important mediators for SLE and CLE, but the mechanisms 
by which IFNs lead to disease are still poorly understood. We aimed to 
investigate how IFN responses in SLE keratinocytes contribute to development of 
CLE. A cohort of 72 RNA sequencing samples from 14 individuals (seven SLE and 
seven healthy controls) were analyzed to study the transcriptomic effects of 
type I and type II IFNs on SLE versus control keratinocytes. In-depth analysis 
of the IFN responses was conducted. Bioinformatics and functional assays were 
conducted to provide implications for the change of IFN response. A significant 
hypersensitive response to IFNs was identified in lupus keratinocytes, including 
genes (IFIH1, STAT1, and IRF7) encompassed in SLE susceptibility loci. Binding 
sites for the transcription factor PITX1 were enriched in genes that exhibit 
IFN-sensitive responses. PITX1 expression was increased in CLE lesions based on 
immunohistochemistry, and by using small interfering RNA knockdown, we 
illustrated that PITX1 was required for upregulation of IFN-regulated genes in 
vitro. SLE patients exhibit increased IFN signatures in their skin secondary to 
increased production and a robust, skewed IFN response that is regulated by 
PITX1. Targeting these exaggerated pathways may prove to be beneficial to 
prevent and treat hyperinflammatory responses in SLE skin.