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

Autor:	Klein B; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Reynolds MB; Department of Microbiology and Immunology, University of Michigan, Ann Arbor., Xu B; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Gharaee-Kermani M; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Gao Y; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Berthier CC; Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States., Henning S; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Loftus SN; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., McNeely KE; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Victory AM; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Dobry C; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Hile GA; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Ma F; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Turnier JL; Division of Pediatric Rheumatology, Department of Pediatrics, University of Michigan, Ann Arbor., Gudjonsson JE; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., O'Riordan MX; Department of Microbiology and Immunology, University of Michigan, Ann Arbor., Kahlenberg JM; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.; Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 26. Date of Electronic Publication: 2024 Jan 26.
DOI:	10.1101/2024.01.23.576771
Abstrakt:	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. Competing Interests: Competing interests: JMK has received grant support from Q32 Bio, Celgene/Bristol-Myers Squibb, Ventus Therapeutics, Rome Therapeutics, and Janssen. JMK has served on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EMD serrano, Gilead, GlaxoSmithKline, Aurinia Pharmaceuticals, Rome Therapeutics, and Ventus Therapeutics. JEG has received support from Eli Lilly, Janssen, BMS, Sanofi, Prometheus, Almirall, Kyowa-Kirin, Novartis, AnaptysBio, Boehringer Ingelheim, Regeneron, AbbVie, and Galderma.
Databáze:	MEDLINE
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