Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury.

Mitochondria are endosymbiotic descendents of bacteria, well tolerated by the eukaryotic cells that they now serve after millions of years of co-evolution. But in extremis it seems strains in the relationship may emerge. Tests on plasma samples from patients who had suffered severe trauma show that mitochondrial DAMPs (or damage-associated molecular patterns) are released into the circulation as a result of tissue damage, where they activate neutrophils via specific formyl peptide receptors. This triggers systemic inflammation, tissue damage and apparent sepsis. These DAMPs interact with receptors that are part of the innate immune response to molecules known as PAMPs (pathogen associated molecular patterns), which are expressed on invading microorganisms, causing bacterial sepsis. This finding appears to explain the apparent sepsis sometimes associated with severe trauma even when no infection is present. Severe trauma can lead to death and sepsis in the absence of apparent infection. Here evidence shows that mitochondrial debris, released from damaged cells, is present in the circulation of seriously injured trauma patients. Such debris is shown to activate neutrophils via specific formyl peptide receptors, triggering systemic inflammation and end organ injury. 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.