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Circulating mitochondrial DAMPs cause inflammatory responses to injury

Nature volume 464, pages 104–107 (2010)Cite this article

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Abstract

Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis1. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors2. Similarly, cellular injury can release endogenous ‘damage’-associated molecular patterns (DAMPs) that activate innate immunity3. Mitochondria are evolutionary endosymbionts that were derived from bacteria4 and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial ‘enemies within’ by cellular injury is a key link between trauma, inflammation and SIRS.

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Figure 1: PMN [Ca2+]i responses to MTD.
Figure 2: MTDs activate PMNs.
Figure 3: Mitochondrial DNA activates PMN through CpG/TLR9 interactions.
Figure 4: MTDs cause systemic inflammation and organ injury in vivo.

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References

  1. Bone, R. C. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). J. Am. Med. Assoc. 268, 3452–3455 (1992)

    Article  CAS  Google Scholar 

  2. Janeway, C. A. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989)

    Article  CAS  Google Scholar 

  3. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994)

    Article  CAS  Google Scholar 

  4. Sagan, L. On the origin of mitosing cells. J. Theor. Biol. 14, 255–274 (1967)

    Article  CAS  Google Scholar 

  5. Sasser, S. M. et al. Guidelines for field triage of injured patients. Recommendations of the National Expert Panel on Field Triage. MMWR Recomm. Rep. 58, 1–35 (2009)

    PubMed  Google Scholar 

  6. Abraham, E. Neutrophils and acute lung injury. Crit. Care Med. 31, S195–S199 (2003)

    Article  Google Scholar 

  7. Fine, J., Frank, E. D., Ravin, H. A., Rutenberg, S. H. & Schweinburg, F. B. The bacterial factor in traumatic shock. N. Engl. J. Med. 260, 214–220 (1959)

    Article  CAS  Google Scholar 

  8. Moore, F. A. et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J. Trauma 31, 629–636, discussion 636–638 (1991)

    Article  CAS  Google Scholar 

  9. Deitch, E. A., Xu, D. & Kaise, V. L. Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front. Biosci. 11, 520–528 (2006)

    Article  CAS  Google Scholar 

  10. Marcker, K. & Sanger, F. N-formyl-methionyl-S-RNA. J. Mol. Biol. 8, 835–840 (1964)

    Article  CAS  Google Scholar 

  11. Taanman, J. W. The mitochondrial genome: structure, transcription, translation and replication. Biochim. Biophys. Acta 1410, 103–123 (1999)

    Article  CAS  Google Scholar 

  12. Baker, S. P., O’Neill, B., Haddon, W. & Long, W. B. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J. Trauma 14, 187–196 (1974)

    Article  CAS  Google Scholar 

  13. Schiffmann, E., Corcoran, B. A. & Wahl, S. M. N-formylmethionyl peptides as chemoattractants for leucocytes. Proc. Natl Acad. Sci. USA 72, 1059–1062 (1975)

    Article  ADS  CAS  Google Scholar 

  14. Rabiet, M. J., Huet, E. & Boulay, F. Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR. Eur. J. Immunol. 35, 2486–2495 (2005)

    Article  CAS  Google Scholar 

  15. Hauser, C. J. et al. Major trauma enhances store-operated calcium influx in human neutrophils. J. Trauma 48, 592–597, discussion 597–598 (2000)

    Article  CAS  Google Scholar 

  16. Tarlowe, M. H. et al. Inflammatory chemoreceptor cross-talk suppresses leukotriene B4 receptor 1-mediated neutrophil calcium mobilization and chemotaxis after trauma. J. Immunol. 171, 2066–2073 (2003)

    Article  CAS  Google Scholar 

  17. West, M. A. et al. Whole blood leukocyte mitogen activated protein kinases activation differentiates intensive care unit patients with systemic inflammatory response syndrome and sepsis. J. Trauma 62, 805–811 (2007)

    Article  CAS  Google Scholar 

  18. Wenzel-Seifert, K. & Seifert, R. Cyclosporin H is a potent and selective formyl peptide receptor antagonist. Comparison with N-t-butoxycarbonyl-L-phenylalanyl-L-leucyl-L-phenylalanyl-L- leucyl-L-phenylalanine and cyclosporins A, B, C, D, and E. J. Immunol. 150, 4591–4599 (1993)

    CAS  PubMed  Google Scholar 

  19. Van Lint, P. & Libert, C. Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 17, 217–223 (2006)

    Article  CAS  Google Scholar 

  20. Cardon, L. R., Burge, C., Clayton, D. A. & Karlin, S. Pervasive CpG suppression in animal mitochondrial genomes. Proc. Natl Acad. Sci. USA 91, 3799–3803 (1994)

    Article  ADS  CAS  Google Scholar 

  21. Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I. M. & Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004)

    Article  CAS  Google Scholar 

  22. Hayashi, F., Means, T. K. & Luster, A. D. Toll-like receptors stimulate human neutrophil function. Blood 102, 2660–2669 (2003)

    Article  CAS  Google Scholar 

  23. Lee, S. H., Lee, J. G., Kim, J. R. & Baek, S. H. Toll-like receptor 9-mediated cytosolic phospholipase A2 activation regulates expression of inducible nitric oxide synthase. Biochem. Biophys. Res. Commun. 364, 996–1001 (2007)

    Article  CAS  Google Scholar 

  24. Uchida, K., Szweda, L. I., Chae, H. Z. & Stadtman, E. R. Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes. Proc. Natl Acad. Sci. USA 90, 8742–8746 (1993)

    Article  ADS  CAS  Google Scholar 

  25. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nature Rev. Immunol. 4, 469–478 (2004)

    Article  CAS  Google Scholar 

  26. Hauser, C. J. et al. PAF-mediated Ca2+ influx in human neutrophils occurs via store-operated mechanisms. J. Leukoc. Biol. 69, 63–68 (2001)

    CAS  PubMed  Google Scholar 

  27. Fekete, Z. et al. Injury-enhanced calcium mobilization in circulating rat neutrophils models human PMN responses. Shock 16, 15–20 (2001)

    Article  CAS  Google Scholar 

  28. Zhang, Q. et al. Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation. Life Sci. 77, 3068–3077 (2005)

    Article  CAS  Google Scholar 

  29. Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006)

    Article  ADS  CAS  Google Scholar 

  30. Hauser, C. J. Preclinical models of traumatic, hemorrhagic shock. Shock 24 (suppl. 1). 24–32 (2005)

    Article  Google Scholar 

Download references

Acknowledgements

This work is supported by a National Institute of General Medical Sciences grant and a Department of Defense CDMRP/DRMRP hypothesis development award (to C.J.H.).

Author Contributions Experiments were conceived and designed by C.J.H., Q.Z., K.I. and W.J. Experiments were performed by Q.Z., M.R., Y.C., Y.S., W.J., K.B. and T.S. Data were analysed by Q.Z. and C.J.H. The paper was written by Q.Z., M.R. and C.J.H.

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Authors and Affiliations

  1. Department of Surgery, Division of Trauma, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA,

    Qin Zhang, Mustafa Raoof, Yu Chen, Yuka Sumi, Tolga Sursal, Wolfgang Junger, Kiyoshi Itagaki & Carl J. Hauser

  2. Trauma Clinical Academic Unit, Barts and the London School of Medicine & Dentistry, Queen Mary, University of London, Whitechapel Road, London E1 1BB, UK ,

    Karim Brohi

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  1. Qin Zhang
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Correspondence to Carl J. Hauser.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-2 and Supplementary Figures 1-7 with Legends. (PDF 1430 kb)

Supplementary Video 1

In this video Human PMN are seen to migrate toward a pipette tip releasing fMLF. (MOV 3503 kb)

Supplementary Video 2

In this video Human PMN migrate toward an identical pipette tip releasing MTD. (MOV 3866 kb)

Supplementary Video 3

In this video Human PMN fail to migrate toward a pipette tip releasing an equal volume of MTD in the presence of the formyl peptide receptor inhibitor cyclosporin H (CsH). (MOV 3863 kb)

Supplementary Video 4

In this video Human PMN fail to migrate toward a pipette tip releasing an equal volume of MTD in the presence of antibodies to formyl peptide receptor-1 (FPR1). (MOV 3865 kb)

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Zhang, Q., Raoof, M., Chen, Y. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). https://doi.org/10.1038/nature08780

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