Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1

• Published in: Frontiers in immunology Vol. 15; p. 1384606
• Main Authors: Loftus, Shannon N, Gharaee-Kermani, Mehrnaz, Xu, Bin, Moore, Tyson M, Hannoudi, Andrew, Mallbris, Mischa J, Klein, Benjamin, Gudjonsson, Johann E, Kahlenberg, J Michelle
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 10.04.2024
• Subjects: Animals; Apoptosis; Caspase 8 - genetics; Caspase 8 - metabolism; Immunology; interferon; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Interferon-alpha - metabolism; keratinocyte; Keratinocytes - metabolism; Keratinocytes - radiation effects; lupus; Mice; Mice, Inbred C57BL; ultraviolet light; Ultraviolet Rays - adverse effects; apoptosis; interferon; keratinocyte; lupus; ultraviolet light
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1384606

Ultraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown. Here, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure. We identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. , overexpression of epidermal resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1). These data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB.