Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria

Busani, Stefano; Biasi, Sara De; Nasi, Milena; Paolini, Annamaria; Venturelli, Sophie; Tosi, Martina; Girardis, Massimo; Cossarizza, Andrea

doi:10.3389/fimmu.2020.00768

Cited by 12 publications

(10 citation statements)

References 21 publications

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“…in addition, mtdna was positively associated with mortality in patients who were hospitalized for up to 28 days. Further studies confirmed these results (32)(33)(34)(35). Additionally, other studies have suggested that mtdna serves a key role in the pathogenesis of severe trauma, major abdominal surgery, acute lung injury (ali)/acute respiratory distress syndrome (ARDS), ischemia/reperfusion (I/R) injury, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus (Sle), myocarditis and myocardial infarction (1,15,19,(36)(37)(38).…”

Section: Mtdnasupporting

confidence: 68%

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Kong

Song

2022

Mol Med Rep

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Mitochondria are key organelles of cellular energy metabolism; both mitochondrial function and metabolism determine the physiological function of cells and serve an essential role in immune responses. Key damage-associated molecular patterns (daMPs), such as mitochondrial dna and n-formyl peptides, released following severe trauma-induced mitochondrial damage may affect the respiratory chain, enhance oxidative stress and activate systemic inflammatory responses via a variety of inflammation-associated signaling pathways. Severe trauma can lead to sepsis, multiple organ dysfunction syndrome and death. The present review aimed to summarize the pathophysiological mechanisms underlying the effects of human mitochondrial injury-released daMPs on triggering systemic inflammatory responses and to determine their potential future clinical applications in preventing and treating sepsis. Contents1. introduction 2. Structure and function of mitochondria 3. mtdaMPs 4. mtdna 5. effect of mtdna on the occurrence and development of SirS 6. nFPs 7. TFaM 8. mtdaMPs and intestinal barrier dysfunction 9. conclusion can

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Section: Mtdnasupporting

confidence: 68%

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Kong

Song

2022

Mol Med Rep

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“…From all animal models, we demonstrated the gut translocation of bacteria-free DNA in sepsis with LPS-bacterial DNA synergy, possibly through the simultaneous TLR-4 and TLR-9 activation on macrophages [49,50]. The profound inflammation induces mitochondrial injury [76,77] and mitochondrial free DNA in systemic circulation, which further facilitate inflammatory responses [78,79] in several immune cells including macrophages [80]. Here, LPS induced M1 macrophage polarization [56], partly through the acceleration of glycolysis, the main energy source of the cells during the hyper-inflammatory stage, despite the reduction in mitochondrial activities (mitochondrial abundance, mtDNA, and maximal respiration), supporting previous publications [81,82].…”

Section: Discussionmentioning

confidence: 99%

Blood Bacteria-Free DNA in Septic Mice Enhances LPS-Induced Inflammation in Mice through Macrophage Response

Kaewduangduen

Visitchanakun

Saisorn

et al. 2022

IJMS

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Although bacteria-free DNA in blood during systemic infection is mainly derived from bacterial death, translocation of the DNA from the gut into the blood circulation (gut translocation) is also possible. Hence, several mouse models with experiments on macrophages were conducted to explore the sources, influences, and impacts of bacteria-free DNA in sepsis. First, bacteria-free DNA and bacteriome in blood were demonstrated in cecal ligation and puncture (CLP) sepsis mice. Second, administration of bacterial lysate (a source of bacterial DNA) in dextran sulfate solution (DSS)-induced mucositis mice elevated blood bacteria-free DNA without bacteremia supported gut translocation of free DNA. The absence of blood bacteria-free DNA in DSS mice without bacterial lysate implies an impact of the abundance of bacterial DNA in intestinal contents on the translocation of free DNA. Third, higher serum cytokines in mice after injection of combined bacterial DNA with lipopolysaccharide (LPS), when compared to LPS injection alone, supported an influence of blood bacteria-free DNA on systemic inflammation. The synergistic effects of free DNA and LPS on macrophage pro-inflammatory responses, as indicated by supernatant cytokines (TNF-α, IL-6, and IL-10), pro-inflammatory genes (NFκB, iNOS, and IL-1β), and profound energy alteration (enhanced glycolysis with reduced mitochondrial functions), which was neutralized by TLR-9 inhibition (chloroquine), were demonstrated. In conclusion, the presence of bacteria-free DNA in sepsis mice is partly due to gut translocation of bacteria-free DNA into the systemic circulation, which would enhance sepsis severity. Inhibition of the responses against bacterial DNA by TLR-9 inhibition could attenuate LPS-DNA synergy in macrophages and might help improve sepsis hyper-inflammation in some situations.

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“…Mitochondria are important for ATP production and mitochondrial free DNA in serum is associated with sepsis severity [ 40 , 56 , 57 ], partly on account of cGAS activation [ 58 ]. Here, impacts of mitochondria on LPS-stimulated WT macrophages were demonstrated by (i) the presence of mitochondria-associated-genes, as determined by RNA sequencing analysis, and (ii) enhanced glycolysis with decreased maximal respiration, as determined with extracellular flux analysis [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

Visitchanakun

Kaewduangduen

Chareonsappakit

et al. 2021

IJMS

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Although the enhanced responses against serum cell-free DNA (cfDNA) in cases of sepsis—a life-threatening organ dysfunction due to systemic infection—are understood, the influence of the cytosolic DNA receptor cGAS (cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase) on sepsis is still unclear. Here, experiments on cGAS deficient (cGAS-/-) mice were conducted using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models and macrophages. Severity of CLP in cGAS-/- mice was less severe than in wildtype (WT) mice, as indicated by mortality, serum LPS, cfDNA, leukopenia, cytokines (TNF-α, IL-6 and IL-10), organ histology (lung, liver and kidney) and spleen apoptosis. With the LPS injection model, serum cytokines in cGAS-/- mice were lower than in WT mice, despite the similar serum cfDNA level. Likewise, in LPS-activated WT macrophages, the expression of several mitochondria-associated genes (as revealed by RNA sequencing analysis) and a profound reduction in mitochondrial parameters, including maximal respiration (determined by extracellular flux analysis), DNA (mtDNA) and mitochondrial abundance (revealed by fluorescent staining), were demonstrated. These data implied the impact of cfDNA resulting from LPS-induced cell injury. In parallel, an additive effect of bacterial DNA on LPS, seen in comparison with LPS alone, was demonstrated in WT macrophages, but not in cGAS-/- cells, as indicated by supernatant cytokines (TNF-α and IL-6), M1 proinflammatory polarization (iNOS and IL-1β), cGAS, IFN-γ and supernatant cyclic GMP–AMP (cGAMP). In conclusion, cGAS activation by cfDNA from hosts (especially mtDNA) and bacteria was found to induce an additive proinflammatory effect on LPS-activated macrophages which was perhaps responsible for the more pronounced sepsis hyperinflammation observed in WT mice compared with the cGAS-/- group.

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Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria

Cited by 12 publications

References 21 publications

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Systemic inflammatory response syndrome is triggered by mitochondrial damage (Review)

Blood Bacteria-Free DNA in Septic Mice Enhances LPS-Induced Inflammation in Mice through Macrophage Response

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

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