Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue
Open accessAbstract
Mitochondrial DNA (mtDNA) contains unmethylated CpG motifs that exhibit immune stimulatory capacities. The aim of this study was to investigate whether mtDNA activates the Toll-like receptor 9 (TLR9)/nuclear factor-κB (NF-κB) pathway, thereby contributing to post-traumatic systemic inflammatory response syndrome (SIRS) and lung injury in rats. The effects of mtDNA on macrophage culture were examined in order to elucidate the putative cellular mechanisms. Rats and macrophage cultures were treated with phosphate-buffered saline, nuclear DNA, or mtDNA for 2, 4, 8 and 24 h. Histological analysis of lung tissue was undertaken following hematoxylin and eosin staining, and cytokine levels were assessed by ELISA. NF-κB and IκB-α phosphorylation levels, as well as TLR9 protein expression were determined by western blot analysis; NF-κB, IκB-α and TLR9 mRNA levels were analyzed by RT-PCR. A greater degree of inflammation and lung injury was observed in response to mtDNA. In addition, mtDNA increased serum tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels in vivo and increased their secretion by cultured macrophages (p<0.05). In lung tissue, mtDNA increased NF-κB, IκB-α and TLR9 mRNA levels (p<0.05); it also increased phosphorylated NF-κB p65 and TLR9 protein levels in the macrophage cultures. Thus, mtDNA may be part of the danger-associated molecular patterns, contributing to the initiation of sterile SIRS through the activation of the TLR9/NF-κB pathway and the induction of pro-inflammatory cytokine production.
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TLR9 interaction with mtDNA activates NF-kB signaling and increases pro-inflammatory cytokine expression.
“Interaction of TLR9 with mtDNA activates the nuclear factor kappa B (NF-jB) signaling and increases the expression of other pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-1b (Julian et al, 2013;Yu & Bennett, 2014;Zhang et al, 2014).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Zhang et al, 2014
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- Authors
- ZHANG, J.-Z., LIU, Z., LIU, J., REN, J.-X., & SUN, T.-S.
- Affiliations
- The Military General Hospital of Beijing PLA (CN)
- Venue
- International Journal of Molecular Medicine
- Publisher
- Spandidos Publications
- Published
- 2014-02-10
- Volume
- 33
- Issue
- 4
- Pages
- 817-824
- ISSN
- 1107-3756 (ISSN-L)
- 1791-244X
- PMC
- PMC3976143
- OpenAlex
- W2165572246
- Cited by
- 194
- References
- 50
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 15 · 2022: 21 · 2021: 23 · 2020: 27 · 2019: 24 · 2018: 22 · 2017: 16 · 2016: 16 · 2015: 12 · 2014: 5
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-02-17)
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- International Journal of Molecular Medicine (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- mitochondrial DNA, TLR9, NF-κB signaling, systemic inflammatory response syndrome, lung injury, macrophages, damage-associated molecular patterns, sterile inflammation, inflammatory cytokines, TNF-α, interleukin-6, IL-10, IκBα phosphorylation, CpG motifs
- MeSH terms
- NF-KappaB Inhibitor alpha, Animals, Cells, Cultured, DNA, Mitochondrial, Gene Expression Regulation, Inflammation, Lung, Macrophages, Male, Phosphorylation, RNA, Messenger, Cytokines, NF-kappa B, Rats, Sprague-Dawley, I-kappa B Proteins, Toll-Like Receptor 9, Rats, Acute Lung Injury
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