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Abstract Number: 1692

Interferon Alpha Promotes Ultraviolet Light-Mediated Keratinocyte Apoptosis in a Caspase-8 Dependent Manner via Upregulation of Interferon Regulatory Factor 1

Shannon Estadt, Mehrnaz Gharaee-Kermani, Bin Xu, Tyson Moore, Andrew Hannoudi and J. Michelle Kahlenberg, University of Michigan, Ann Arbor, MI

Meeting: ACR Convergence 2022

Keywords: Apoptosis, Cutaneous, interferon, Systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 14, 2022

Title: Innate Immunity Poster: Basic and Translational Science

Session Type: Poster Session D

Session Time: 1:00PM-3:00PM

Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by enhanced sensitivity to ultraviolet radiation (UVR). UVR can trigger cutaneous and systemic disease flares, yet mechanisms driving these responses are not yet fully characterized. Type I interferons (IFNs) are overexpressed in non-lesional SLE skin compared to healthy control skin and promote increased death of SLE keratinocytes after UVR, however, the way they do so is unknown. This study explores activation and regulation of cell death pathways in keratinocytes exposed to type I IFNs and UVR.

Methods: N/TERTs, an immortalized human keratinocyte line, were treated with IFN-alpha (IFNα) overnight, then exposed to UVB light (0-50mJ/cm2). Four hours post UVB, cells were stained with Annexin V (AV) and propidium iodide (PI) or cleaved caspase-3 (CC3) and fixable viability dye (FVD) and analyzed by flow cytometry. Cells were pretreated with apoptosis, necroptosis, and pyroptosis inhibitors or neutralizing antibodies to examine activation of cell death pathways. Genetic knockdowns were generated in N/TERTs by using lentiviral shRNA vectors (for XAF1 knockdown) or Accell siRNA (for IRF1 knockdown). Knockdown efficiency was determined by Western blot or quantitative reverse transcription PCR. For IRF1 knockdown experiments, caspase-3 activation was measured by microscopy six hours post UVB exposure using the CellEvent Caspase-3/7 Green Detection Reagent.

Results: Four hours post UVB exposure, IFNα priming significantly increased the percentage of CC3+FVD– and AV+PI– cells compared to treatment with UVB alone. Inhibiting RIPK1, RIPK3, or caspase-1 had no effect on death suggesting no involvement of necroptosis or pyroptosis. Pan-caspase or caspase-8 inhibition significantly reduced death following combination treatment with IFNα and UVB, while caspase-9 inhibition did not, suggesting enhanced activation of the extrinsic pathway of apoptosis. RNA-sequencing identified pro-apoptotic genes XAF1, TNFSF10 (encodes TRAIL), and IRF1 as highly upregulated by IFNα treatment in primary keratinocytes. Intriguingly, neither genetic knockdown of XAF1 nor inhibition of TRAIL via neutralizing antibody treatment blocked the IFN-mediated increase in UVB-induced apoptosis. siRNA-mediated knockdown of IRF1 blocked the IFN-induced enhancement of apoptosis following UVB exposure.

Conclusion: Treatment of keratinocytes with IFNα results in increased sensitivity to UVB-mediated cell death, which takes the primary form of caspase-8 driven apoptosis. This IFN-mediated effect is dependent on the transcription factor IRF1. It is well documented that SLE patients have elevated levels of circulating and cutaneous type I IFNs that are a prominent feature of the disease. Together, these data suggest that photosensitive responses exhibited by SLE patients may be due to type I IFN priming of keratinocytes that drives IRF1 expression and sensitizes cells to increased apoptosis after minimal exposures to UVB. Continued investigation into mechanisms by which this occurs will provide important prophylactic options to prevent SLE flares.


Disclosures: S. Estadt, None; M. Gharaee-Kermani, None; B. Xu, None; T. Moore, None; A. Hannoudi, None; J. Kahlenberg, AstraZeneca, Bristol-Myers Squibb(BMS), Eli Lilly, GlaxoSmithKlein(GSK), Janssen, Merck/MSD, Gilead.

To cite this abstract in AMA style:

Estadt S, Gharaee-Kermani M, Xu B, Moore T, Hannoudi A, Kahlenberg J. Interferon Alpha Promotes Ultraviolet Light-Mediated Keratinocyte Apoptosis in a Caspase-8 Dependent Manner via Upregulation of Interferon Regulatory Factor 1 [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/interferon-alpha-promotes-ultraviolet-light-mediated-keratinocyte-apoptosis-in-a-caspase-8-dependent-manner-via-upregulation-of-interferon-regulatory-factor-1/. Accessed .
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