Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal derived interferon kappa

Abstract

Objective:

Skin inflammation and photosensitivity are common in cutaneous (CLE) and systemic lupus erythematosus (SLE) patients, yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I IFN and photosensitive responses and examine its dysregulation in lupus skin.

Methods:

mRNA expression of type I IFN genes was analyzed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts, and endothelial cells was analyzed via RNA-seq. IFNK KO keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. UVB-mediated apoptosis was analyzed via TUNEL staining. in vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin.

Results:

IFNK is one of two type I IFNs significantly increased (1.5-fold change, FDR q<0.001) in lesional CLE skin. GO analysis showed that type I IFN responses were enriched (FDR=6.8×10 ⁻⁰⁴) in keratinocytes not in fibroblast and endothelial cells and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, knock-out of IFN-κ or inhibition of IFN signaling with baricitinib, abrogates UVB-induced apoptosis.

Conclusion:

Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.