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Danger signals from mitochondrial DAMPS in trauma and post-injury sepsis

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Abstract

In all multicellular organisms, immediate host responses to both sterile and infective threat are initiated by very primitive systems now grouped together under the general term ‘danger responses’. Danger signals are generated when primitive ‘pattern recognition receptors’ (PRR) encounter activating ‘alarmins’. These molecular species may be of pathogenic infective origin (pathogen-associated molecular patterns) or of sterile endogenous origin (danger-associated molecular patterns). There are many sterile and infective alarmins and there is considerable overlap in their ability to activate PRR, but in all cases the end result is inflammation. It is the overlap between sterile and infective signals acting via a relatively limited number of PRR that generally underlies the great clinical similarity we see between sterile and infective systemic inflammatory responses. Mitochondria (MT) are evolutionarily derived from bacteria, and thus they sit at the crossroads between sterile and infective danger signal pathways. Many of the molecular species in mitochondria are alarmins, and so the release of MT from injured cells results in a wide variety of inflammatory events. This paper discusses the known participation of MT in inflammation and reviews what is known about how the major.

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References

  1. Schweinburg FB, Seligman AM, Fine J. Transmural migration of intestinal bacteria. N Engl J Med. 1950;242:747–51.

    Article  PubMed  CAS  Google Scholar 

  2. Moore FA, Moore EE, Poggetti R, et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma. 1991;31:629–36 (discussion 636–8).

    Google Scholar 

  3. Janeway CA. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1–13.

    Article  PubMed  Google Scholar 

  4. Oppenheim JJ, Yang D. Alarmins: chemotactic activators of immune responses. Curr Opin Immunol. 2005;17:359–65.

    Article  PubMed  CAS  Google Scholar 

  5. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.

    Article  PubMed  CAS  Google Scholar 

  6. Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA;268:3452–5.

  7. Faist E, Hartl WH, Baue AE. [Immune mechanisms of post-traumatic hyperinflammation and sepsis]. Immun Infekt. 1994;22:203–13.

    PubMed  CAS  Google Scholar 

  8. Hauser CJ, Zhou X, Joshi P, et al. The immune microenvironment of human fracture/soft-tissue hematomas and its relationship to systemic immunity. J Trauma. 1997;42:895–903. discussion 903–4.

    Article  PubMed  CAS  Google Scholar 

  9. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016;16:378–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Croce MA, Brasel KJ, Coimbra R, et al. National Trauma Institute prospective evaluation of the ventilator bundle in trauma patients: does it really work? J Trauma Acute Care Surg. 2013;74:354–60 (discussion 360–2).

    Article  Google Scholar 

  12. Michetti CP, Fakhry SM, Ferguson PL, et al. Ventilator-associated pneumonia rates at major trauma centers compared with a national benchmark: a multi-institutional study of the AAST. J Trauma Acute Care Surg. 2012;72:1165–73.

    Article  PubMed  Google Scholar 

  13. Dolezal P, Likic V, Tachezy J, et al. Evolution of the molecular machines for protein import into mitochondria. Science. 2006;313:314–8.

    Article  PubMed  CAS  Google Scholar 

  14. Dyall SD, Brown MT, Johnson PJ. Ancient invasions: from endosymbionts to organelles. Science. 2004;304:253–7.

    Article  PubMed  CAS  Google Scholar 

  15. Andersson SGE, Karlberg O, Canbäck B, et al. On the origin of mitochondria: a genomics perspective. Philos Trans R Soc Lond B Biol Sci. 2003;358:165–77; (discussion 177–9).

    Article  CAS  Google Scholar 

  16. Fang C, Wei X, Wei Y. Mitochondrial DNA in the regulation of innate immune responses. Protein Cell. 2016;7:11–6.

    Article  PubMed  CAS  Google Scholar 

  17. Takeshita F, Gursel I, Ishii KJ, et al. Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9. Semin Immunol. 2004;16:17–22.

    Article  PubMed  CAS  Google Scholar 

  18. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709–60.

    Article  PubMed  CAS  Google Scholar 

  19. Nakahira K, Kyung S-Y, Rogers AJ, et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013;10:e1001577; (discussion e1001577).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Kaczmarek E, Hauser CJ, Kwon WY, Rica I, Chen L, Sandler N, Otterbein LE, Campbell Y, Cook CH, Yaffe MB, Marusich M, Itagaki K. A subset of five human Mitochondrial formyl peptides mimics bacterial peptides and functionally deactivates human neutrophils. J Trauma Acute Care Surg. https://doi.org/10.1097/TA.0000000000001971 (in press).

  21. Dosch M, Gerber J, Jebbawi F, et al. Mechanisms of ATP release by inflammatory cells. Int J Mol Sci. https://doi.org/10.3390/ijms19041222 (19. Epub Ahead of Print April 18, 2018).

  22. Little JP, Simtchouk S, Schindler SM, et al. Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia. Mol Cell Neurosci. 2014;60:88–96.

    Article  PubMed  CAS  Google Scholar 

  23. Krysko DV, Agostinis P, Krysko O, et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 2011;32:157–64.

    Article  PubMed  CAS  Google Scholar 

  24. Simmons JD, Lee Y-L, Mulekar S, et al. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg. 2013;258:591–6. (discussion 596-8).

    PubMed  Google Scholar 

  25. Crouser ED, Shao G, Julian MW, et al. Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors. Crit Care Med. 2009;37:2000–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Aichbichler BW, Petritsch W, Reicht GA, et al. Anti-cardiolipin antibodies in patients with inflammatory bowel disease. Dig Dis Sci. 1999;44:852–6.

    Article  PubMed  CAS  Google Scholar 

  27. Pinti M, Cevenini E, Nasi M, et al. Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm-aging”. Eur J Immunol. 2014;44:1552–62.

    Article  PubMed  CAS  Google Scholar 

  28. Wagener FADTG., van Beurden HE, von den Hoff JW, et al. The heme-heme oxygenase system: a molecular switch in wound healing. Blood. 2003;102:521–8.

    Article  PubMed  CAS  Google Scholar 

  29. Pullerits R, Bokarewa M, Jonsson I-M, et al. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology. 2005;44:32–9.

    Article  PubMed  CAS  Google Scholar 

  30. Wilkins HM, Weidling IW, Ji Y, et al. Mitochondria-derived damage-associated molecular patterns in neurodegeneration. Front Immunol. 2017;8:508.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Sursal T, Stearns-Kurosawa DJ, Itagaki K, et al. Plasma bacterial and mitochondrial DNA distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates. Shock. 2013;39:55–62.

    PubMed  PubMed Central  Google Scholar 

  32. Raymond SL, Holden DC, Mira JC, et al. Microbial recognition and danger signals in sepsis and trauma. Biochim Biophys Acta. 2017;1863:2564–73.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang Q, Itagaki K, Hauser CJ. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock. 2010;34:55–9.

    Article  PubMed  CAS  Google Scholar 

  34. Davidson BA, Vethanayagam RR, Grimm MJ, et al. NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury. J Immunol. 2013;190:1714–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Szczesny B, Marcatti M, Ahmad A, et al. Mitochondrial DNA damage and subsequent activation of Z-DNA binding protein 1 links oxidative stress to inflammation in epithelial cells. Sci Rep. 2018;8:914.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Safdar A, Tarnopolsky MA. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a029827 (8. Epub ahead of print March 1, 2018).

  37. Lood C, Blanco LP, Purmalek MM, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22:146–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Meyer JN, Hartman JH, Mello DF. Mitochondrial toxicity. Toxicol Sci. 2018;162:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rodriguez A-M, Nakhle J, Griessinger E, et al. Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle. 2018;1–25.

  40. Sinclair KA, Yerkovich ST, Hopkins PM-A, et al. Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Res Ther. 2016;7:91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Berridge MV, Herst PM, Rowe MR, et al. Mitochondrial transfer between cells: Methodological constraints in cell culture and animal models. Anal Biochem. https://doi.org/10.1016/j.ab.2017.11.008 (Epub ahead of print November 21, 2017).

  42. Sun S, Sursal T, Adibnia Y, et al. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS One. 2013;8:e59989.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Collins LV, Hajizadeh S, Holme E, et al. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol. 2004;75:995–1000.

    Article  PubMed  CAS  Google Scholar 

  44. Mathew A, Lindsley TA, Sheridan A, et al. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis. 2012;30:617–27.

    Article  PubMed  CAS  Google Scholar 

  45. Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kuck JL, Obiako BO, Gorodnya OM, et al. Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs. Am J Physiol Lung Cell Mol Physiol. 2015;308:L1078-85.

    Article  PubMed  CAS  Google Scholar 

  47. Raoof M, Zhang Q, Itagaki K, et al. Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J Trauma. 2010;68:1328–32; (discussion 1332–4).

    Article  PubMed  CAS  Google Scholar 

  48. Henikoff S, Henikoff JG. Performance evaluation of amino acid substitution matrices. Proteins. 1993;17:49–61.

    Article  PubMed  CAS  Google Scholar 

  49. Hvidberg V, Maniecki MB, Jacobsen C, et al. Identification of the receptor scavenging hemopexin-heme complexes. Blood. 2005;106:2572–9.

    Article  PubMed  CAS  Google Scholar 

  50. Nielsen MJ, Møller HJ, Moestrup SK. Hemoglobin and heme scavenger receptors. Antioxid Redox Signal. 2010;12:261–73.

    Article  PubMed  CAS  Google Scholar 

  51. Otterbein LE, Foresti R, Motterlini R. Heme oxygenase-1 and carbon monoxide in the heart: the balancing act between danger signaling and pro-survival. Circ Res. 2016;118:1940–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Larsen R, Gozzelino R, Jeney V, et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med. 2010;2:51ra71.

    Article  PubMed  CAS  Google Scholar 

  53. Ferreira A, Balla J, Jeney V, et al. A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med (Berl). 2008;86:1097–111.

    Article  CAS  Google Scholar 

  54. Gouveia Z, Carlos AR, Yuan X, et al. Characterization of plasma labile heme in hemolytic conditions. FEBS J. 2017;284:3278–301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Porto BN, Alves LS, Fernández PL, et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem. 2007;282:24430–6.

    Article  PubMed  CAS  Google Scholar 

  56. Belcher JD, Young M, Chen C, et al. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood. 2013;122:2757–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Di Virgilio F, Sarti AC, Grassi F. Modulation of innate and adaptive immunity by P2X ion channels. Curr Opin Immunol. 2018;52:51–9.

    Article  PubMed  CAS  Google Scholar 

  58. Giuliani AL, Sarti AC, Falzoni S, et al. The P2 × 7 receptor-interleukin-1 Liaison. Front Pharmacol. 2017;8:123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Hasan D, Blankman P, Nieman GF. Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury. Purinergic Signal. 2017;13:363–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Maguire JJ, Tyurina YY, Mohammadyani D, et al. Known unknowns of cardiolipin signaling: the best is yet to come. Biochim Biophys Acta. 2017;1862:8–24.

    Article  PubMed  CAS  Google Scholar 

  61. Chakraborty K, Raundhal M, Chen BB, et al. The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun. 2017;8:13944.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Rani M, Nicholson SE, Zhang Q, et al. Damage-associated molecular patterns (DAMPs) released after burn are associated with inflammation and monocyte activation. Burns. 2017;43:297–303.

    Article  PubMed  Google Scholar 

  63. Gouveia A, Bajwa E, Klegeris A. Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. Biochim Biophys Acta. 2017;1861:2274–81.

    Article  PubMed  CAS  Google Scholar 

  64. McDonald B, Pittman K, Menezes GB, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330:362–6.

    Article  PubMed  CAS  Google Scholar 

  65. Zhao C, Itagaki K, Gupta A, et al. Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses. J Trauma Acute Care Surg. 2014;76:1222–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Itagaki K, Riça I, Zhang J, et al. Intratracheal instillation of neutrophils rescues bacterial overgrowth initiated by trauma damage-associated molecular patterns. J Trauma Acute Care Surg. 2017;82:853–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tarlowe MH, Duffy A, Kannan KB, et al. Prospective study of neutrophil chemokine responses in trauma patients at risk for pneumonia. Am J Respir Crit Care Med. 2005;171:753–9.

    Article  PubMed  Google Scholar 

  68. Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010;9:728–43.

    Article  PubMed  CAS  Google Scholar 

  69. Wegiel B, Otterbein LE. Go green: the anti-inflammatory effects of biliverdin reductase. Front Pharmacol. 2012;3:47.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lee BH, Hwang DM, Palaniyar N, et al. Activation of P2 × (7) receptor by ATP plays an important role in regulating inflammatory responses during acute viral infection. PLoS One. 2012;7:e35812.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Kagan VE, Bayır H, Tyurina YY, et al. Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Biochem Biophys Res Commun. 2017;482:482–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

Funded by the United States Department of Defense focused program award W81XWH-16-1-0464.

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  1. Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    C. J. Hauser & L. E. Otterbein

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Hauser, C.J., Otterbein, L.E. Danger signals from mitochondrial DAMPS in trauma and post-injury sepsis. Eur J Trauma Emerg Surg 44, 317–324 (2018). https://doi.org/10.1007/s00068-018-0963-2

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