title: Circulating mitochondrial DAMPs cause inflammatory responses to injury.
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.
authors.affiliation: Department of Surgery, Division of Trauma, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Mustafa
authors.initials: M
authors.lastname: Raoof
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumi
authors.forename: Tolga
authors.initials: T
authors.lastname: Sursal
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Junger
authors.forename: Karim
authors.initials: K
authors.lastname: Brohi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000473:pathology; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D004272:DNA, Mitochondrial / Q000097:blood / Q000276:immunology; D005269:Femur / Q000293:injuries; D050723:Fractures, Bone / Q000276:immunology / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000293:injuries / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014947:Wounds and Injuries / Q000097:blood / Q000150:complications* / Q000276:immunology* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D044042:Receptors, Formyl Peptide; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020928:Mitogen-Activated Protein Kinases