Abstract Text: Photosensitivity is a characteristic of skin diseases such as cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). The exact cause of photosensitivity is unclear, but it is believed that the sensitivity of keratinocytes (KCs) to UVB radiation may play a role, as the epidermis absorbs UVB radiation. Our single-cell RNA sequencing on skin samples of patients with CLE and DM revealed a robust type-I-interferon (IFN-I) signature in basal KCs, even in non-lesional skin, suggesting subclinical priming for subsequent inflammatory insults. ELISA analysis of interstitial skin fluid from DM patients showed elevated levels of IFN-beta.
To investigate how IFN-Is affect KC death after UVB irradiation, in vitro assays were conducted. The study found that pyroptosis, not cell lysis, is the primary mechanism of UVB-induced inflammatory death in KCs, mediated through the host-encoded pore-forming protein gasderminE (GSDME). Furthermore, GSDME cleavage occurs in a caspase 3 (CASP3)-dependent manner. ZAK-alpha knockout KCs showed a significant reduction in cleaved CASP3 and GSDME, suggesting ribotoxic stress as a mechanism of UVB-induced KC pyroptosis.
We also found that pretreatment of KCs with type I IFNs increased pyroptosis through a GSDME/CASP3-independent mechanism following UVB exposure, which was inhibited by pan-caspase inhibition. Bulk-RNA sequencing of KCs identified upregulation of apoptotic-related genes, including TXNIP, GCH1, and ATF3, after treatment with type I IFNs, suggesting them as targets that could prime KC sensitivity to UVB.
These findings shed light on the underlying mechanisms of UVB photosensitivity in IFN-I-mediated skin diseases.