UV-mediated and mitochondrial stress responses in the pathogenesis of cutaneous lupus erythematosus
Final Report Abstract
UV light represents a well-known trigger for cutaneous inflammation in systemic and cutaneous lupus erythematosus (LE). Central mediators in the pathogenesis of LE are type I interferons (IFN), which are upregulated both in lesional and non-lesional LE skin. The aim of this work was to investigate mitochondrial stress after UV radiation in LE skin and to understand how IFN priming enhances epidermal inflammatory responses. In this project, we investigated the interaction of DNA in the Z conformation (Z-DNA) with Z-DNA binding protein 1 (ZBP1). We were able to show for the first time that keratinocytes (KCs) exposed to UV harbor mitochondrial damage resulting in the release of mitochondrial Z-DNA. UVB generates mitochondrial Z-DNA via the generation of reactive oxygen species, which promote the configurational change from B-DNA to Z-DNA through oxidative damage to DNA. Furthermore, after UV exposure, mitochondrial Z-DNA is released into the cytosol, where it can be recognized by sensors of the innate immune system. IFN priming of KCs leads to a stabilization of the Z-DNA by inducing the sensor ZBP1. ZBP1 is overexpressed in the skin of photosensitive diseases such as LE and dermatomyositis and correlates with the IFN signature. Single cell sequencing demonstrated that ZBP1 is mainly upregulated in basal KCs, a highly relevant cell type for absorbing UV radiation. Confocal microscopy and proximity ligation assay confirmed interaction of Z-DNA with ZBP1. Notably, inhibition of ZBP1 in KCs reduced expression of UV-induced cytokines and chemokines. In contrast, a genetic upregulation of ZBP1 resulted in a chronic upregulation of IFN, similar to that seen in LE KCs. 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. Hence, inhibition of the ligand (Z-DNA) or receptor (ZBP1) represents a potential new therapeutic approach for photosensitive autoimmune diseases including LE and dermatomyositis. In addition, a collaboration investigated the extent to which chronic cutaneous IFN favors infections with Staphylococcus aureus, which was shown to be more abundant in LE lesions. We demonstrated that IFN leads to an adaptation of metabolism in macrophages, which reduces secretion of proinflammatory cytokines. This mechanism is dependent on IFN-induced nitric oxide synthase (iNOS). Importantly, cutaneous MRSA infection in IFNK TG mice promoted impaired wound healing, vasculopathy and lung infection. In summary, this work funded by the German Research Foundation has been a successful career investment with numerous publications in the field of UV and IFN biology. We identified central mechanisms of autoimmune photosensitivity in LE and the consequences of an epidermal IFN signature on systemic immune responses to UV light and during cutaneous infections.
Publications
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A critical role for IFN-β signaling for IFN-κ induction in keratinocytes. Frontiers in Lupus, 2.
Xu, Bin; Musai, Jon; Tan, Yee Sun; Hile, Grace A.; Swindell, William R.; Klein, Benjamin; Qin, J. Tingting; Sarkar, Mrinal K.; Gudjonsson, Johann E. & Kahlenberg, J. Michelle
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Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity. openRxiv.
Klein, Benjamin; Reynolds, Mack B.; Xu, Bin; Gharaee-Kermani, Mehrnaz; Gao, Yiqing; Berthier, Celine C.; Henning, Svenja; Loftus, Shannon N.; McNeely, Kelsey E.; Victory, Amanda M.; Dobry, Craig; Hile, Grace A.; Ma, Feiyang; Turnier, Jessica L.; Gudjonsson, Johann E.; O’Riordan, Mary X. & Michelle, Kahlenberg J.
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Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1. Frontiers in Immunology, 15.
Loftus, Shannon N.; Gharaee-Kermani, Mehrnaz; Xu, Bin; Moore, Tyson M.; Hannoudi, Andrew; Mallbris, Mischa J.; Klein, Benjamin; Gudjonsson, Johann E. & Kahlenberg, J. Michelle
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Keratinocytes – Amplifiers of Immune Responses in Systemic Lupus Erythematosus. Current Rheumatology Reports, 27(1).
Klein, Benjamin; Nguyen, Nguyen Thi Kim; Moallemian, Rezvan & Kahlenberg, J. Michelle
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Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection. Cell Reports, 43(8), 114607.
Reynolds, Mack B.; Klein, Benjamin; McFadden, Michael J.; Judge, Norah K.; Navarrete, Hannah E.; Michmerhuizen, Britton C.; Awad, Dominik; Schultz, Tracey L.; Harms, Paul W.; Zhang, Li; O’Meara, Teresa R.; Sexton, Jonathan Z.; Lyssiotis, Costas A.; Kahlenberg, J. Michelle & O’Riordan, Mary X.
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UV-induzierte Pathogenese des Lupus erythematodes. Die Dermatologie, 75(7), 528-538.
Kurz, Bernadett; Klein, Benjamin; Berneburg, Mark & Meller, Stephan
