Circulating mitochondrial DAMPs cause inflammatory responses to injury
Qin Zhang, Mustafa Raoof, Yu Chen, Yuka Sumi, Tolga Sursal, Wolfgang Junger, Karim Brohi, Kiyoshi Itagaki, Carl J Hauser, Qin Zhang, Mustafa Raoof, Yu Chen, Yuka Sumi, Tolga Sursal, Wolfgang Junger, Karim Brohi, Kiyoshi Itagaki, Carl J Hauser
Abstract
Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria 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 Ca(2+) 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.
Figures
References
- Bone RC. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome) JAMA. 1992;268:3452–5.
- Janeway CA., Jr Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13.
- Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.
- Sagan L. On the origin of mitosing cells. J Theor Biol. 1967;14:255–74.
- Sasser SM, et al. Guidelines for field triage of injured patients. Recommendations of the National Expert Panel on Field Triage. MMWR Recomm Rep. 2009;58:1–35.
- Abraham E. Neutrophils and acute lung injury. Crit Care Med. 2003;31:S195–9.
- Fine J, Frank ED, Ravin HA, Rutenberg SH, Schweinburg FB. The bacterial factor in traumatic shock. N Engl J Med. 1959;260:214–20.
- Moore FA, 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.
- Deitch EA, Xu D, Kaise VL. Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front Biosci. 2006;11:520–8.
- Marcker K, Sanger F. N-Formyl-Methionyl-S-Rna. J Mol Biol. 1964;8:835–40.
- Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta. 1999;1410:103–23.
- Baker SP, O’Neill B, Haddon W, Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974;14:187–96.
- Schiffmann E, Corcoran BA, Wahl SM. N-formylmethionyl peptides as chemoattractants for leucocytes. Proc Natl Acad Sci U S A. 1975;72:1059–62.
- Rabiet MJ, 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. 2005;35:2486–95.
- Hauser CJ, et al. Major trauma enhances store-operated calcium influx in human neutrophils. J Trauma. 2000;48:592–7. discussion 597–8.
- Tarlowe MH, et al. Inflammatory chemoreceptor cross-talk suppresses leukotriene B4 receptor 1-mediated neutrophil calcium mobilization and chemotaxis after trauma. J Immunol. 2003;171:2066–73.
- West MA, et al. Whole blood leukocyte mitogen activated protein kinases activation differentiates intensive care unit patients with systemic inflammatory response syndrome and sepsis. J Trauma. 2007;62:805–11.
- 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. 1993;150:4591–9.
- Van Lint P, Libert C. Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 2006;17:217–23.
- Cardon LR, Burge C, Clayton DA, Karlin S. Pervasive CpG suppression in animal mitochondrial genomes. Proc Natl Acad Sci U S A. 1994;91:3799–803.
- Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol. 2004;75:995–1000.
- Hayashi F, Means TK, Luster AD. Toll-like receptors stimulate human neutrophil function. Blood. 2003;102:2660–2669.
- Lee SH, Lee JG, Kim JR, Baek SH. Toll-like receptor 9-mediated cytosolic phospholipase A2 activation regulates expression of inducible nitric oxide synthase. Biochem Biophys Res Commun. 2007;364:996–1001.
- Uchida K, Szweda LI, Chae HZ, Stadtman ER. Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes. Proc Natl Acad Sci U S A. 1993;90:8742–6.
- Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4:469–78.
- Hauser CJ, et al. PAF-mediated Ca2+ influx in human neutrophils occurs via store-operated mechanisms. J Leukoc Biol. 2001;69:63–8.
- Fekete Z, et al. Injury-enhanced calcium mobilization in circulating rat neutrophils models human PMN responses. Shock. 2001;16:15–20.
- Zhang Q, et al. Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation. Life Sci. 2005;77:3068–77.
- Chen Y, et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science. 2006;314:1792–5.
- Hauser CJ. Preclinical models of traumatic, hemorrhagic shock. Shock. 2005;24 (Suppl 1):24–32.
Source: PubMed