Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9–p38 MAPK pathway

Gu, Xiaoling; Wu, Guannan; Yao, Yanwen; Zeng, Junli; Shi, Da–Hua; Lv, Tangfeng; Luo, Liang; Song, Yong

doi:10.1016/j.freeradbiomed.2015.02.034

Cited by 74 publications

(65 citation statements)

References 28 publications

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“…MtDNA was showed to skew endotheliocytes and cardiomyocytes to an inflammatory feature and involved in atherosclerosis, hypertension, myocarditis and dilated cardiomyopathy induced by pressure overload [21, 22, 36]. MtDNA can provoke the immune response directly via the activation of TLR9, and the following NF-κB signaling increases the expression of other pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β [12, 20, 22]. Nakahira et al showed that increased mitochondria reactive oxygen species (mROS) and NLRP3 activation in ATP or LPS stimulated macrophages promoted the release of mtDNA into the cytosol, which in turn activated NLRP3 inflammasome and mediated the secretion of IL-1β and IL-18, ultimately participated in the induction of inflammatory disease [12].…”

Section: Discussionmentioning

confidence: 99%

“…Several immune cells including monocytes and granulocytes could be activated by mtDNA and present an inflammatory phenotype [18, 19]. In isolated rat lungs, exogenous administration of mtDNA could recapitulate the clinical phenotype of acute respiratory distress syndrome, which was abrogated by the simultaneous administration of TLR9 blocker [20]. Recently, mtDNA has been discovered to play a growing role in cardiovascular diseases [11].…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mitochondrial DNA (mtDNA), acting as a newly found ‘danger-associated molecular patterns’ (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. Methods: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. Results: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and up-regulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. Conclusion: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

et al. 2017

Cell Physiol Biochem

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“…Thus, cf-mtDNA can interact with TLR9 extracellularly and intracellularly when released into the cytosol internally or internalised via microparticle engulfment. TLR9 interaction results in p38 MAPK activation and downstream pro-inflammatory cytokine release and NET formation [1, 16, 17, 51]. …”

Section: Mitochondrial Dna: Pathways To Inflammationmentioning

confidence: 99%

“…In this review, we consider this to include exposed cf-mtDNA fragments, mitochondrial DNA (mtDNA) contained within vesicles and microparticles or extruded whole mitochondria. cf-mtDNA gained interest as a trigger of inflammation due to its similarity to bacterial DNA, its ability to stimulate innate immune responses through Toll-like receptor 9 (TLR-9) and its ability to induce tissue injury when injected in animal models [1, 2]. Numerous pathological states such as after trauma, cancer, mental illness and degenerative disease have been associated with measurable increases of plasma mtDNA [3–9].…”

Section: Introductionmentioning

confidence: 99%

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

Thurairajah

Briggs

Balogh

2018

Eur J Trauma Emerg Surg

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Mitochondria play a key role in the pathophysiology of post-injury inflammation. Cell-free mitochondrial DNA (cf-mtDNA) is now understood to catalyse sterile inflammation after trauma. Observations in trauma cohorts have identified high cf-mtDNA in patients with systemic inflammatory response syndrome and multiple organ failure as well as following major surgery. The source of cf-mtDNA can be various cells affected by mechanical and hypoxic injury (passive mechanism) or induced by inflammatory mechanisms (active mechanism). Multiple forms of cf-mtDNA exist; mtDNA fragments, mtDNA in microparticles/vesicles and cell-free mitochondria. Trauma to cells that are rich in mitochondria are believed to release more cf-mtDNA. This review describes the current understanding of the mechanisms of cf-mtDNA release, its systemic effects and the potential therapeutic implications related to its modification. Although current understanding is insufficient to change trauma management, focussed research goals have been identified to pave the way for monitoring and manipulation of cf-mtDNA release and effects in trauma.

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“…Concerning the S100 protein family, both S100A9 and S100A12 (EN-RAGE) are increased in BALF of patients with acute respiratory distress syndrome (ARDS) compared with healthy controls (27,28), although no studies have been undertaken to investigate the effects of neutralization of HSPs or S100 proteins in VILI. Concerning nucleic acids, previous studies have shown that acid aspiration results in profoundly increased mtDNA level in BALF of mice (29), and that exogenous administration of mtDNA in the lungs or circulation of rats and mice elicits inflammatory lung injury in a TLR9-dependent manner (30,31). However, the effect of endogenous mtDNA release or neutralization during mechanical ventilation and its role in ventilator-induced inflammation has not yet been investigated.…”

Section: Ventilator-induced Lung Injurymentioning

confidence: 99%

Danger in the Intensive Care Unit

Timmermans

Kox²,

Scheffer³

et al. 2016

Shock

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Danger-associated molecular patterns (DAMPs) that are released by injured, threatened, or dead cells, or that originate from the extracellular matrix, influence the immune system. This is of great relevance in critically ill patients, in whom trauma or surgery-related cell damage, hypoxia, ischemia, and infections can result in extensive release of DAMPs. As many patients at the intensive care unit suffer from immune system-related complications, DAMPs could serve as markers for the prognosis of these patients and represent possible therapeutic targets. In the present review, we provide an overview of several well known DAMPs (high-mobility group box 1, heat-shock proteins, s100 proteins, nucleic acids, and hyaluronan) and their effects on the immune system. Furthermore, we discuss the role of DAMPs as markers or therapeutic targets in several conditions frequently encountered in critically ill patients, such as sepsis, trauma, ventilator-induced lung injury, and cardiac arrest.

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Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9–p38 MAPK pathway

Cited by 74 publications

References 28 publications

The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

Danger in the Intensive Care Unit

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