Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury

Hotz, Meghan; Qing, Danielle; Shashaty, Michael G. S.; Zhang, Peggy; Faust, H; Sondheimer, Neal; Rivella, Stefano; Worthen, G. Scott; Mangalmurti, Nilam S.

doi:10.1164/rccm.201706-1161oc

Cited by 113 publications

(113 citation statements)

References 42 publications

(53 reference statements)

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“…This damage-associated pattern can activate toll-like receptors leading to a systemic inflammatory response syndrome. [40][41][42] Studies in various patients indeed revealed a higher cell-free mtDNA copy number in patients with clinical outcomes. 22,43,44 Strengths and limitations of the study To our knowledge, this is largest reported study of mtDNA copy numbers in CKD patients using prespecified and centrally adjudicated outcome measures.…”

Section: Oxidative Stress As a Possible Explanation Of The Findingsmentioning

confidence: 98%

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease

Fazzini¹,

Lamina²,

Fendt³

et al. 2019

Kidney International

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Section: Oxidative Stress As a Possible Explanation Of The Findingsmentioning

confidence: 98%

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease

Fazzini¹,

Lamina²,

Fendt³

et al. 2019

Kidney International

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“…We quantified mtDNA levels from blood samples drawn at ED presentation and 48 h by using polymerase chain reaction for the mitochondrial ND1 gene, measured in triplicate, as reported previously; log-transformed copy number per microliter was used to ensure normality. 24 Primary and Secondary Outcomes ARDS was defined as previously described applying the Berlin criteria, utilizing data over the first 6 days following presentation. 25 All chest radiographs were assessed by two trained reviewers (J. P. R. and M. G. S. S.).…”

Section: Mtdna Measurementmentioning

confidence: 99%

“…This study does not prove that circulating mtDNA causes ARDS; in fact, lung injury could result in elevated circulating mtDNA at 48 h, although our finding that patients with sepsis and a pulmonary infection source had no mtDNA-ARDS association argues against this reverse causal effect, as does the substantial preclinical evidence from animal models. 7,8,24,36,37 Our ability to identify whether mtDNA is elevated prior to ARDS incidence was limited by the lack of samples available between presentation and 48 h. Further research detailing early plasma mtDNA dynamics during critical illness will help to identify the earliest association and infer a causal relationship between circulating mtDNA and ARDS, a necessary step to inform the potential value of mtDNA pathwayspecific therapies. Nevertheless, this study provides compelling evidence linking mtDNA and ARDS.…”

Section: Messi Cohort: Sepsismentioning

confidence: 99%

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Faust

Reilly

Anderson

et al. 2020

Chest

Self Cite

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BACKGROUND: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.METHODS: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.RESULTS: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/mL; 95% CI, 1.14-2.19 [P ¼ .006]; sepsis: OR, 1.52/log copies/ mL; 95% CI, 1.12-2.06 [P ¼ .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/mL; 95% CI, 1.36-3.55 [P ¼ .001], n ¼ 69) than those with a pulmonary source (OR, 1.04/log copies/mL; 95% CI, 0.68-1.59 [P ¼ .84], n ¼ 51; P ¼ .014 for interaction).CONCLUSIONS: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS. CHEST 2020; 157(1):67-76

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“…Dengue virus (DENV) infection induces the release of mtDNA into the cytosol, which upregulates TLR9 expression, binds TLR9 and translocates together with TLR9 into lysosomes to trigger downstream signaling events [26]. Interestingly, in response to the proinflammatory characteristics of mtDNA and to prevent further damage to tissues or organs, such as the lung, red blood cells can bind mtDNA through TLR9 to maintain homeostasis [27]. Another commonly recognized sensor of mtDNA is cyclic GMP-AMP synthase (cGAS), which shares similarities with the antiviral cytosolic double-stranded RNA sensor 2′-5′-oligoadenylate synthase (OAS1) [28].…”

Section: Downregulation Of Mitochondrial Dna (Mtdna)mentioning

confidence: 99%

Operation of mitochondrial machinery in viral infection-induced immune responses

Lai

Luo

2018

Biochemical Pharmacology

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Mitochondria have been recognized as ancient bacteria that contain evolutionary endosymbionts. Metabolic pathways and inflammatory signals interact within mitochondria in response to different stresses, such as viral infections. In this commentary, we address several interesting questions, including (1) how do mitochondrial machineries participate in immune responses; (2) how do mitochondria mediate antiviral immunity; (3) what mechanisms involved in mitochondrial machinery, including the downregulation of mitochondrial DNA (mtDNA), disturbances of mitochondrial dynamics, and the induction of mitophagy and regulation of apoptosis, have been adopted by viruses to evade antiviral immunity; (4) what mechanisms involve the regulation of mitochondrial machineries in antiviral therapeutics; and (5) what are the potential challenges and perspectives in developing mitochondria-targeting antiviral treatments? This commentary provides a comprehensive review of the roles and mechanisms of mitochondrial machineries in immunity, viral infections and related antiviral therapeutics.

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Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury

Abstract: RBCs homeostatically bind mtDNA, and RBC-mediated DNA scavenging is essential in mitigating lung injury after CpG-DNA. Our data suggest a role for RBCs in regulating lung inflammation during disease states where cf-mtDNA is elevated, such as sepsis and trauma.

Cited by 113 publications

References 42 publications

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease

Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Operation of mitochondrial machinery in viral infection-induced immune responses

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