IFNγ Causes Keratinocyte Necroptosis in Acute Graft-Versus-Host Disease

Freund, Lukas; Oehrl, Stephanie; Schwingen, Julius; Haeberle, Stefanie; Döbel, Thomas; Lee, Paul D.H.; Meisel, Stefan; Mihalceanu, Silvia; Rußwurm, Martin; Luft, Thomas; Schäkel, Knut

doi:10.1016/j.jid.2023.02.025

Cited by 3 publications

(1 citation statement)

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“…Thus, the IFN milieu could act as a “switch” which toggles the function of ZBP1 towards IFN secretion and apoptosis and away from panoptotic cell death. In contrast, diseases with increases in IFNγ show enhanced necroptosis of keratinocytes( 66 ). Of note, ZBP1 can also activate the inflammasome via interaction with AIM2, ASC and pyrin to result in IL1β secretion( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity

Klein,

Reynolds,

et al. 2024

Preprint

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Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. Here, we show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV)B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is significantly upregulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. Strikingly, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cGAS-STING activation compared to B-DNA. ZBP1 knockdown abrogates UV-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.

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Section: Discussionmentioning

confidence: 99%