1178 Mechanisms of type I interferon-mediated UVB sensitivity in human keratinocytes

Photosensitivity is a characteristic feature of some inflammatory skin diseases, including cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). Among the various hypotheses that explain this phenomenon, an aberrant sensitivity keratinocytes (KC) deserves more attention, especially in case UVB photosensitivity, as epidermis almost entirely absorbs UVB. However, underlying mechanisms UVB-induced KC death milieu are unknown. Single-cell RNA sequencing on specimens from healthy volunteers patients with CLE DM showed robust type-I-interferon (IFN-I) signature basal KC, even non-lesional skin, suggesting subclinical priming for subsequent insults. ELISA interstitial fluid revealed elevated levels IFN-beta. We, therefore, sought to investigate how IFN-Is affect after irradiation. Usingin vitroassays, we found pyroptosis, not cell lysis, primary mechanism KCs, which was mediated through host-encoded pore-forming protein gasderminE (GSDME). Further, discovered GSDME cleavage happens caspase 3 (CASP3)-dependent manner. Using ZAK-alpha knockout significant reduction cleaved CASP3 GSDME, ribotoxic stress pyroptosis. Pretreatment cultured type I IFNs (IFN-alpha beta) (p<0.0001) but IFN-gamma enhanced GSDME-mediated pyroptosis led increased release interleukin-1 cytokine (p=0.01) following exposure, blunted by pan-caspase inhibition. Bulk-RNA identified upregulation apoptotic-related genes, TXNIP, GCH1, ATF3, treatment IFNs, them targets could prime These findings provide insight into photosensitivity IFN-I-mediated diseases.