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Mitochondrial DNA: An Endogenous Trigger for Immune Paralysis
Simon T Schäfer1, Lars Franken, Michael Adamzik
1From the Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (S.T.S., M.A., A.E., N.S., J.W., J.P.); Institut für molekulare Medizin und experimentelle Immunologie, Universität Bonn, Bonn, Germany (L.F., C.K.); Klinik für Anästhesiologie und operative Intensivmedizin, Knappschaftskrankenhaus Bochum und Ruhruniversität Bochum, Bochum, Germany (M.A.); Institut für Medizinische Mikrobiologie, Immunologie und Parasitologie, Universität Bonn, Bonn, Germany (B.S.); Klinische Epidemiologie, Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen - Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Jena, Germany (A.S.); Klinik und Poliklinik für Dermatologie und Allergologie, Universität Bonn, Bonn, Germany (S.K., T.B.); Institut für Pathologie, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (H.A.B.); Institut für Medizinische Mikrobiologie, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (J.S., A.M.W.); Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany (J.F., S.F.); Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany (S.F.); and Klinik für Orthopädie und Unfallchirurgie, Universitätsklinikum Bonn, Bonn, Germany (A.L.).
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.
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