Mitochondrial DNA: An Endogenous Trigger for Immune Paralysis.
In: Anesthesiology, Jg. 124 (2016-04-01), Heft 4, S. 923-933
Online
academicJournal
Zugriff:
Background: Critically ill patients are at high risk to suffer from sepsis, even in the absence of an initial infectious source, but the molecular mechanisms for their increased sepsis susceptibility, including a suppressed immune system, remain unclear. Although microbes and pathogen-associated molecular pattern are accepted inducers of sepsis and septic immunosuppression, the role of endogenous Toll-like receptor (TLR) ligands, such as mitochondrial DNA (mtDNA), in altering the immune response is unknown. Methods: Mitochondrial DNA serum concentrations of the mitochondrial genes D-Loop and adenosine triphosphatase 6 were determined (quantitative polymerase chain reaction) in 165 septic patients and 50 healthy volunteers. Furthermore, cytotoxic T-cell activity was analyzed in wild-type and TLR9 knockout mice, with/without previous mtDNA administration, followed by injection of an ovalbumin-expressing adenoviral vector. Results: Mitochondrial DNA serum concentrations were increased in septic patients (adenosine triphosphatase 6, 123-fold; D-Loop, 76-fold, P < 0.0001) compared with volunteers. Furthermore, a single mtDNA injection caused profound, TLR9-dependent immunosuppression of adaptive T-cell cytotoxicity in wild-type but not in TLR9 knockout mice and evoked various immunosuppressive mechanisms including the destruction of the splenic microstructure, deletion of cross-presenting dendritic cells, and up-regulation of programmed cell death ligand 1 and indoleamine 2,3-dioxygenase. Several of these findings in mice were mirrored in septic patients, and mtDNA concentrations were associated with an increased 30-day mortality. Conclusions: The findings of this study imply that mtDNA, an endogenous danger associated molecular pattern, is a hitherto unknown inducer of septic immunoparalysis and one possible link between initial inflammation and subsequent immunosuppression in critically ill patients. [ABSTRACT FROM AUTHOR]
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Mitochondrial DNA: An Endogenous Trigger for Immune Paralysis.
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Autor/in / Beteiligte Person: | Schäfer, Simon T. ; Franken, Lars ; Adamzik, Michael ; Schumak, Beatrix ; Scherag, André ; Engler, Andrea ; Schönborn, Niels ; Walden, Jennifer ; Koch, Susanne ; Baba, Hideo A. ; Steinmann, Jörg ; Westendorf, Astrid M. ; Fandrey, Joachim ; Bieber, Thomas ; Kurts, Christian ; Frede, Stilla ; Peters, Jürgen ; Limmer, Andreas |
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Zeitschrift: | Anesthesiology, Jg. 124 (2016-04-01), Heft 4, S. 923-933 |
Veröffentlichung: | 2016 |
Medientyp: | academicJournal |
ISSN: | 0003-3022 (print) |
DOI: | 10.1097/ALN.0000000000001008 |
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