The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
MITOCHONDRIAL DNA IS RELEASED BY SHOCK AND ACTIVATES NEUTROPHILS VIA P38 MAP KINASE
Abstract
Bacterial DNA (bDNA) can activate an innate-immune stimulatory "danger" response via toll-like receptor 9 (TLR9). Mitochondrial DNA (mtDNA) is unique among endogenous molecules in that mitochondria evolved from prokaryotic ancestors. Thus, mtDNA retains molecular motifs similar to bDNA. It is unknown, however, whether mtDNA is released by shock or is capable of eliciting immune responses like bDNA. We hypothesized shock-injured tissues might release mtDNA and that mtDNA might act as a danger-associated molecular pattern (or "alarmin") that can activate neutrophils (PMNs) and contribute to systemic inflammatory response syndrome. Standardized trauma/hemorrhagic shock caused circulation of mtDNA as well as nuclear DNA. Human PMNs were incubated in vitro with purified mtDNA or nuclear DNA, with or without pretreatment by chloroquine (an inhibitor of endosomal receptors like TLR9). Neutrophil activation was assessed as matrix metalloproteinase (MMP) 8 and MMP-9 release as well as p38 and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation. Mitochondrial DNA induced PMN MMP-8/MMP-9 release and p38 phosphorylation but did not activate p44/42. Responses were inhibited by chloroquine. Nuclear DNA did not induce PMN activation. Intravenous injection of disrupted mitochondria (mitochondrial debris) into rats induced p38 MAPK activation and IL-6 and TNF-alpha accumulation in the liver. In summary, mtDNA is released into the circulation by shock. Mitochondrial DNA activates PMN p38 MAPK, probably via TLR9, inducing an inflammatory phenotype. Mitochondrial DNA may act as a danger-associated molecular pattern or alarmin after shock, contributing to the initiation of systemic inflammatory response syndrome.
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Cites
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“These data strongly suggest that mtDNA activates PMNs in part via TLR9.”
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“Many hypotheses have been advanced to explain the relationship between shock and inflammation including Bmicrocirculatory dysfunction[ (25, 26) and Bgut origin sepsis[ (27, 28).”
Background
Cited by
Mitochondria in innate immune responses
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Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs
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Origins, structures, and functions of circulating DNA in oncology
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Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation
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Metadata
- Authors
- Zhang, Q., Itagaki, K., & Hauser, C. J.
- Venue
- Shock
- Published
- 2010-07
- Volume
- 34
- Issue
- 1
- Pages
- 55-59
- ISSN
- 1073-2322 (ISSN-L)
- OpenAlex
- W2029821423
- Cited by
- 354
- References
- 32
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- closed
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