Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

Akbari, Mansour; Shanley, Daryl P.; Bohr, Vilhelm A.; Rasmussen, Lene Juel

doi:10.3390/cells10123544

Cited by 17 publications

(7 citation statements)

References 227 publications

(279 reference statements)

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“…It has been reported that unrepaired DNA damage will accelerate the rate of aging [ 39 ]. mtDNA begins to damage over time, and the ability of cells to produce energy is gradually lost, leading to aging [ 40 ]. Mitochondria, known as the power plant of cells, produce 90% of chemical energy to maintain cell survival [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Liu

Li²,

Zheng³

et al. 2022

J Inflamm

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Backgrounds Chronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD are still challenging until now. Elevated serum uric acid(SUA) levels seem to be associated with the inflammatory level in patients with COPD. However, the underlying mechanism is not yet clearly established. In the current research, we aim to elucidate the effect of high SUA levels on airway inflammation among COPD patients. Methods Through bioinformatic analysis, the common potential key genes were determined in both COPD and hyperuricemia (HUA) patients. A total of 68 COPD patients aged 50—75-year were included in the study, and their clinical parameters, including baseline characteristics, lung function test, as well as blood chemistry test were recorded. These parameters were then compared between the COPD patients with and without HUA. Hematoxylin & Eosin (HE), immunofluorescence (IF), and Masson trichrome staining were performed to demonstrate the pathological changes in the lung tissues. Furthermore, we isolated extracellular vesicles (EVs) from plasma, sputum, and bronchoalveolar lavage fluid (BALF) samples and detected the expression of inflammatory factor (Interleukin-6 (IL-6), IL-8 and COPD related proteases (antitrypsin and elastase) between two groups. Additionally, we treated the human bronchial epithelial (HBE) cells with cigarette smoke extract (CSE), and EVs were derived from the plasma in vitro experiments. The critical pathway involving the relationship between COPD and HUA was eventually validated based on the results of RNA sequencing (RNA-seq) and western blot (WB). Results In the study, the COPD patients co-existing with HUA were found to have more loss of pulmonary function compared with those COPD patients without HUA. The lung tissue samples of patients who had co-existing COPD and HUA indicated greater inflammatory cell infiltration, more severe airway destruction and even fibrosis. Furthermore, the high SUA level could exacerbate the progress of airway inflammation in COPD through the transfer of EVs. In vitro experiments, we determined that EVs isolated from plasma, sputum, and BALF played pivotal roles in the CSE-induced inflammation of HBE. The EVs in HUA patients might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway. Conclusion The pulmonary function and clinical indicators of COPD patients with HUA were worse than those without HUA, which may be caused by the increased airway inflammatory response through the EVs in the patient's peripheral blood. Moreover, it might mediate the EVs via senescence-related pathways in COPD patients with HUA.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Liu

Li²,

Zheng³

et al. 2022

J Inflamm

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“…Advancing age has been reported to be linked to a condition of chronic low-grade inflammation in various tissues ( 9 ), which is known as “inflammaging” and characterized by elevated levels of circulating pro-inflammatory mediators ( 10 ), including the cytokines interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 ( 11 , 12 ). As an important transcription factor for apoptosis, immunity, and inflammation ( 13 ), nuclear factor-kappa B (NF-κB), as a decisive molecule in muscle atrophy ( 14 ), has been illustrated to be activated in multiple organs of the elderly and aging animals, including aged muscles ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of acupuncture on the miR-146a-mediated IRAK1/TRAF6/NF-κB signaling pathway in rats with sarcopenia induced by D-galactose

Jin¹,

Yang²,

Liu³

et al. 2023

Ann Transl Med

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Background Sarcopenia during aging is closely linked to sterile, low-grade, chronic inflammation. However, considering the increasingly aging global population, the effectiveness of existing treatments for sarcopenia is not exact, and acupuncture, as an effective anti-inflammatory therapy, has the potential to treat it. Methods Fifty Sprague-Dawley rats were randomly allocated into five groups, including Control group, D-galactose (D-gal) group, D-gal + acupuncture (DA) group, D-gal + non-acupoint (DN) group and D-gal amino acid mixture (DAA) group. An aging rat was model constructed using D-gal for 12 weeks. Rats in the control group received 0.9% physiological saline daily. Treatment groups were acupunctured or given amino acid mixture interventions daily, and lasted for last 4 consecutive weeks. The effects of acupuncture were evaluated by the hematoxylin and eosin staining (H&E), transmission electron microscopic (TEM) examination and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The anti-inflammatory mechanism of acupuncture was studied by using the expressions of microRNA-146a (miR-146a) mediated nuclear factor-kappa B (NF-κB) signaling pathway-related proteins were detected by immunofluorescence, western blotting, quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Results Rats injected by D-galactose (D-gal) revealed apparent skeletal muscle atrophy with significantly reduced cross-sectional area and fiber diameter. In contrast, acupuncture treatment alleviated these hallmarks of skeletal muscle atrophy and mitigated the mitochondrial aberrations and skeletal muscle apoptosis in D-gal rats. In addition, acupuncture also downgraded the overexpression of inflammatory factors in skeletal muscle, influenced miR-146a and the target genes level, and inhibited NF-κB nuclear translation in D-gal rats. Conclusions Acupuncture may ameliorate skeletal muscle atrophy, and its effects may be associated with the control of mitochondrial function regulation and the suppression of inflammation.

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“…The order of events leading to mitochondrial dysfunction in APTX deficient cells are currently unclear. However, it is known that loss of function of APTX leads to decreased ATP synthesis, increased DNA damage (particularly in mitochondria), increased ROS production and alterations in mitochondrial morphology, all are functions which have profound effect on normal cell function, including the release of self-DNA into the cytosol (Akbari et al, 2021). The presence of self-and foreign DNA in the cytosol can lead to immune responses and inflammation, which are activated by DNA sensing pathways including cGAS-STING signaling (Gregg et al, 2019;Akbari et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The DNA repair enzyme, aprataxin, plays a role in innate immune signaling

Madsen,

Pease,

Scanlan

et al. 2023

Front. Aging Neurosci.

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Ataxia with oculomotor apraxia type 1 (AOA1) is a progressive neurodegenerative disorder characterized by a gradual loss of coordination of hand movements, speech, and eye movements. AOA1 is caused by an inactivation mutation in the APTX gene. APTX resolves abortive DNA ligation intermediates. APTX deficiency may lead to the accumulation of 5’-AMP termini, especially in the mitochondrial genome. The consequences of APTX deficiency includes impaired mitochondrial function, increased DNA single-strand breaks, elevated reactive oxygen species production, and altered mitochondrial morphology. All of these processes can cause misplacement of nuclear and mitochondrial DNA, which can activate innate immune sensors to elicit an inflammatory response. This study explores the impact of APTX knockout in microglial cells, the immune cells of the brain. RNA-seq analysis revealed significant differences in the transcriptomes of wild-type and APTX knockout cells, especially in response to viral infections and innate immune pathways. Specifically, genes and proteins involved in the cGAS-STING and RIG-I/MAVS pathways were downregulated in APTX knockout cells, which suggests an impaired immune response to cytosolic DNA and RNA. The clinical relevance of these findings was supported by analyzing publicly available RNA-seq data from AOA1 patient cell lines. Comparisons between APTX-deficient patient cells and healthy control cells also revealed altered immune responses and dysregulated DNA- and RNA-sensing pathways in the patient cells. Overall, this study highlights the critical role of APTX in regulating innate immunity, particularly in DNA- and RNA-sensing pathways. Our findings contribute to a better understanding of the underlying molecular mechanisms of AOA1 pathology and highlights potential therapeutic targets for this disease.

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Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

Cited by 17 publications

References 227 publications

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway

Effects of acupuncture on the miR-146a-mediated IRAK1/TRAF6/NF-κB signaling pathway in rats with sarcopenia induced by D-galactose

The DNA repair enzyme, aprataxin, plays a role in innate immune signaling

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