Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.
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We thank X. Sun, L. Tanaka (both at University of Washington), and E. Moore (National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIAMS) for technical assistance; W. Wang (University of Washington) for providing mouse mitochondria isolated from hearts; D. Kuhns (NIAID) for scientific input, and R. Siegel (NIAMS) for critical review of the manuscript. We also thank H.-W. Sun, M. Ward (both at NIAMS) and C. Spiekerman (University of Washington) for expert statistical advice. We also thank M. Gale for providing Tmem173-knockout mice. The study was supported by grants from the Washington Research Foundation, Leap for Lupus (K.B.E.), the Wenner-Gren Foundation, the foundation BLANCEFLOR Boncompagni-Ludovisi née Bildt (C.L.), and the Intramural Research Program at NIAMS/NIH (L.P.B., M.P., C.K.S., C.C.-R. and M.J.K.). The funding bodies had no part in the study design; the collection, analysis and interpretation of the data; the writing of the manuscript or the submission.
The authors declare no competing financial interests.
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Lood, C., Blanco, L., Purmalek, M. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22, 146–153 (2016). https://doi.org/10.1038/nm.4027
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