Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease

• Published in: Nature medicine Vol. 22; no. 2; pp. 146 - 153
• Main Authors: Lood, Christian, Blanco, Luz P, Purmalek, Monica M, Carmona-Rivera, Carmelo, De Ravin, Suk S, Smith, Carolyne K, Malech, Harry L, Ledbetter, Jeffrey A, Elkon, Keith B, Kaplan, Mariana J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2016; Nature Publishing Group
• Subjects: 13/31; 14/63; 38; 38/77; 59; 631/250/2504; 64; 64/60; 692/699/249/1313/1613; Adult; Animals; Antigen-Antibody Complex; Autoimmune diseases; Biomedicine; Cancer Research; DNA, Mitochondrial - metabolism; Extracellular Traps - immunology; Extracellular Traps - metabolism; Female; Granulomatous Disease, Chronic - genetics; Granulomatous Disease, Chronic - immunology; Granulomatous Disease, Chronic - metabolism; Humans; Immunoprecipitation; In Vitro Techniques; Infectious Diseases; Interferon Type I - immunology; Jurkat Cells; Kidney - immunology; Kidney - metabolism; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Male; Metabolic Diseases; Mice; Microscopy, Fluorescence; Mitochondria - metabolism; Mitochondrial DNA; Molecular Medicine; NADPH Oxidases - genetics; Neurons; Neurosciences; Neutrophils - immunology; Oxidation-Reduction; Oxidative stress; Pathogenesis; Peroxidase - metabolism; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Ribonucleoproteins
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4027

Lupus-like disease is driven by NETs enriched in mitochondrial DNA. 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.