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

被引：1326

作者：

Lood, Christian ^{[1
]}

Blanco, Luz P. ^{[2
]}

Purmalek, Monica M. ^{[2
]}

Carmona-Rivera, Carmelo ^{[2
]}

De Ravin, Suk S. ^{[3
]}

Smith, Carolyne K. ^{[2
]}

Malech, Harry L. ^{[3
]}

Ledbetter, Jeffrey A. ^{[4
]}

Elkon, Keith B. ^{[1
,4
]}

Kaplan, Mariana J. ^{[2
]}

机构：

[1] Univ Washington, Div Rheumatol, Seattle, WA 98195 USA

[2] NIAMSD, System Autoimmun Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[3] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA

[4] Univ Washington, Dept Immunol, Seattle, WA 98195 USA

来源：

NATURE MEDICINE | 2016年 / 22卷 / 02期

关键词：

PEPTIDYLARGININE DEIMINASE INHIBITION; NLRP3; INFLAMMASOME; OXIDATIVE DAMAGE; MACROPHAGES; DEFICIENCY; ACTIVATION; IMMUNITY; CELLS;

D O I：

10.1038/nm.4027

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 mitochondria! 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. Mitochondria! 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 granulornatous 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 mitochondria! DNA in autoimmune diseases.

引用

页码：146 / 153

页数：8

共 54 条

[1]

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement [J].