Mitochondrial Dna Is Released by Shock and Activates Neutrophils via P38 Map Kinase

Zhang, Qin; Itagaki, Kiyoshi; Hauser, Carl J.

doi:10.1097/shk.0b013e3181cd8c08

Cited by 298 publications

(283 citation statements)

References 29 publications

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“…Plasma levels of mtDNA are elevated in patients with trauma, and mtDNA released from shockinjured tissues induced neutrophil activation and contributed to systematic inflammatory response syndrome, probably via TLR9, as revealed in trauma models. 12,18,24 However, it remains controversial as to whether the level of mtDNA is elevated and related to death in patients with sepsis. [24][25][26][27] Here, we first showed that the levels of mtDNA are elevated in the systemic circulation and peritoneal cavity from the early phase of polymicrobial peritonitis but not endotoxemia.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, endogenous mitochondrial DNA (mtDNA) was recently shown to activate the TLR9 pathway. 12 Therefore, we hypothesized that endogenous mtDNA might be released into the extracellular space in much greater amounts than LPS, which would amplify innate immunity and kidney injury via binding to TLR9 after CLP. To evaluate this hypothesis, we first evaluated the amount of circulating mtDNA after CLP.…”

mentioning

confidence: 99%

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Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

Tsuji¹,

Tsuji²,

Ohashi³

et al. 2015

JASN

122

113

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Toll-like receptor 9 (TLR9) contributes to the development of polymicrobial septic AKI. However, the mechanisms that activate the TLR9 pathway and cause kidney injury during sepsis remain unknown. To determine the role of mitochondrial DNA (mtDNA) in TLR9-associated septic AKI, we established a cecal ligation and puncture (CLP) model of sepsis in wild-type (WT) and Tlr9-knockout (Tlr9KO) mice. We evaluated systemic circulation and peritoneal cavity dynamics and immune response and tubular mitochondrial dysfunction to determine upstream and downstream effects on the TLR9 pathway, respectively. CLP increased mtDNA levels in the plasma and peritoneal cavity of WT and Tlr9KO mice in the early phase, but the increase in the peritoneal cavity was significantly higher in Tlr9KO mice than in WT mice. Concomitantly, leukocyte migration to the peritoneal cavity increased, and plasma cytokine production and splenic apoptosis decreased in Tlr9KO mice compared with WT mice. Furthermore, CLP-generated renal mitochondrial oxidative stress and mitochondrial vacuolization in the proximal tubules in the early phase were reversed in Tlr9KO mice. To elucidate the effects of mtDNA on immune response and kidney injury, we intravenously injected mice with mitochondrial debris (MTD), including substantial amounts of mtDNA. MTD caused an immune response similar to that induced by CLP, including upregulated levels of plasma IL-12, splenic apoptosis, and mitochondrial injury, but this effect was attenuated by Tlr9KO. Moreover, MTD-induced renal mitochondrial injury was abolished by DNase pretreatment. These findings suggest that mtDNA activates TLR9 and contributes to cytokine production, splenic apoptosis, and kidney injury during polymicrobial sepsis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

Tsuji¹,

Tsuji²,

Ohashi³

et al. 2015

JASN

122

113

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“…Unlike cf-DNA, mtDNA is a critical activator of inflammation and the innate immune system. These free mitochondrial nucleotides act as an "alarmin" or Damage Associated Molecular Patterns (DAMPs) when released into the circulation [29,30]. Mitochondrial DAMPs express at least two molecular signatures, formyl peptides and mtDNA that act on formyl peptide receptors and Toll-like receptor 9 respectively [31].…”

Section: Discussionmentioning

confidence: 99%

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Natarajan¹

2014

J Pulm Respir Med

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Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis.Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured.Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups. Conclusion:Ascorbic acid infusion may improve sepsis outcomes by reducing cf-and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.

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“…Nevertheless, antibacterial activity of released mitochondrial chromatin was demonstrated for eosinophil extracellular traps, but not for NETs. The extracellular release of mitochondrial DNA can also activate neutrophils by functioning as a TLR9 ligand, 83 while delaying constitutive apoptosis. 84 The release of mitochondrial NETs from viable neutrophils is nevertheless very surprising for three reasons: the very small amounts of mitochondria in these cells; the small size of the mitochondrial genome; the absence of antimicrobial histones in such NETs.…”

Section: Release Of Nets By Live Neutrophilsmentioning

confidence: 99%

Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality

et al. 2011

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Neutrophil extracellular traps (NETs) are chromatin structures loaded with antimicrobial molecules. They can trap and kill various bacterial, fungal and protozoal pathogens, and their release is one of the first lines of defense against pathogens. In vivo, NETs are released during a form of pathogen-induced cell death, which was recently named NETosis. Ex vivo, both dead and viable neutrophils can be stimulated to release NETs composed of either nuclear or mitochondrial chromatin, respectively. In certain pathological conditions, NETs are associated with severe tissue damage or certain auto-immune diseases. This review describes the recent progress made in the identification of the mechanisms involved in NETosis and discusses its interplay with autophagy and apoptosis. Cell Death and Differentiation (2011) 18, 581-588; doi:10.1038/cdd.2011.1; published online 4 February 2011Neutrophils have an essential role in innate immunity and are the first cells recruited to the site of infection.1 Human neutrophils are the most abundant leukocytes. They have a very short lifespan, and neutrophil homeostasis is maintained by continuous release of many neutrophils from the bone marrow. Accelerated neutrophil death decreases neutrophil counts (neutropenia) and increases susceptibility to infection. In turn, delayed neutrophil death increases neutrophil counts (neutrophilia) and intensifies innate defenses, possibly promoting chronic inflammation.2 Neutrophils perform their function by engulfing microorganisms or opsonized particles and degrading them by various molecules, and also release lytic enzymes that destroy extracellular pathogens.3 Moreover, they release structures called neutrophil extracellular traps (NETs) that can trap and kill microbes. 4 The neutrophil lifespan constitutes a sensitive balance between their function as effecter cells and their potential to inflict tissue damage. In the absence of inflammatory stimuli, neutrophils continuously undergo apoptosis within 24-48 h both in vivo and in cell culture. The large amounts of superoxide produced by the membrane-associated NADPH oxidase in neutrophils have a central role in the destruction of invading pathogens as well as in the resolution of inflammation. [5][6][7][8][9] Congenital defects that prevent NADPH oxidase activity result in chronic granulomatous disease (CGD), which is characterized by exaggerated immune responses 10 and recurrent life-threatening infections by a narrow set of microorganisms. 11 We recently found that formation of NETs by activated neutrophils requires not only NADPH-oxidasemediated superoxide production, but also autophagy. 12In this review, we present an overview of the main biochemical and morphological features observed during neutrophil activation and discuss in more detail the contribution of NADPH oxidase, histone citrullination, intracellular calcium levels and autophagy to chromatin decondensation and NET formation. Release of Extracellular TrapsIn 2004, the group of Brinkman and Zychlinsky was the first to report the rele...

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Mitochondrial Dna Is Released by Shock and Activates Neutrophils via P38 Map Kinase

Cited by 298 publications

References 29 publications

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality

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