Circulating mitochondrial DAMPs cause inflammatory responses to injury

• Published in: Nature Vol. 464; no. 7285; pp. 104 - 107
• Main Authors: Zhang, Qin, Itagaki, Kiyoshi, Raoof, Mustafa, Sursal, Tolga, Sumi, Yuka, Junger, Wolfgang, Chen, Yu, Hauser, Carl J, Brohi, Karim
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-03-2010; Nature Publishing Group
• Subjects: 631/208/726/2129; 692/420/256; 692/420/2780/262; 692/699/578; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Animals; Bacterial proteins; Biological and medical sciences; Calcium Signaling; Cells, Cultured; CpG Islands - immunology; Deoxyribonucleic acid; DNA; DNA, Mitochondrial - blood; DNA, Mitochondrial - immunology; Femur - injuries; Fractures; Fractures, Bone - immunology; Fractures, Bone - pathology; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; Immunity, Innate - immunology; Infection; Inflammation; letter; Liver - immunology; Liver - injuries; Liver - pathology; Male; Mitochondria - immunology; Mitochondria - secretion; Mitochondrial DNA; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; multidisciplinary; Muscle, Skeletal - immunology; Muscle, Skeletal - pathology; N-Formylmethionine Leucyl-Phenylalanine - immunology; N-Formylmethionine Leucyl-Phenylalanine - metabolism; Neutrophils - enzymology; Neutrophils - immunology; Neutrophils - metabolism; Pattern recognition; Peptides; Phosphorylation; Physiological aspects; Rats; Rats, Sprague-Dawley; Receptors, Formyl Peptide - metabolism; Rheumatoid arthritis; Risk factors; Science; Science (multidisciplinary); Sepsis - immunology; Sepsis - metabolism; Sepsis - microbiology; Systemic Inflammatory Response Syndrome - blood; Systemic Inflammatory Response Syndrome - complications; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - pathology; Toll-Like Receptor 9 - metabolism; Trauma; Wounds and Injuries - blood; Wounds and Injuries - complications; Wounds and Injuries - immunology; Wounds and Injuries - pathology; United Kingdom; Natural immunity; Mitochondria; Inflammation; Immune response; Immunity; Pathogen Associated Molecular Patterns
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08780

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 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.