Interferon Alpha Promotes Extrinsic Apoptosis Of Keratinocytes Following Exposure To Ultraviolet B Radiation

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by sensitivity to ultraviolet radiation (UVR). UVR triggers cutaneous and systemic disease flares, yet mechanisms driving this are not well characterized. Type I interferons (IFNs) are overexpressed in non lesional SLE skin and promote death of SLE keratinocytes (KCs) after UVR, but the manner in which they do so is not known. This study explores activation and regulation of cell death pathways in KCs exposed to type I IFNs and UVR. We treated immortalized human KCs (N/TERTs) overnight with IFNα prior to UVB exposure. Four hours post UVB, IFNα priming significantly increased the percentage of cleaved-caspase-3+ (CC3+) and Annexin V+ propidium iodide− (AV+PI−) cells compared to treatment with UVB alone. Further, IFNα promoted apoptosis at a lower dose of UVB. Inhibiting RIP1, RIP3, or caspase-1 had no effect on death suggesting no involvement of necroptosis or pyroptosis. Use of a pan-caspase inhibitor or a caspase-8 inhibitor significantly reduced AV+PI− cells following IFNα and UVB treatment while caspase-9 inhibition did not, suggesting enhanced activation of extrinsic apoptosis. Treatment with IFNα increased expression of the death ligand TRAIL, an inducer of extrinsic apoptosis. Further studies will determine if IFN-induced upregulation of TRAIL is responsible for UVB-enhanced apoptosis in an autocrine fashion. Together, these data suggest that photosensitive responses exhibited by SLE patients may be due to type I IFN priming of KCs that sensitizes cells to undergo increased extrinsic apoptosis after minimal exposures to UVB. Continued investigation into mechanisms by which this occurs will provide important prophylactic options to prevent SLE flares.