Molecular Assassins From Within: Intracellular DAMPs From Injured Cells Initiate Tissue Infammation
CITATION Ahrens S, Lelenay S, Sancho D, Hanč P, Kjaer S, Feest C, et al. F-actin is an evolutionarily conserved damage-asssociated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 2012; 36: 635–645.
CITATION Land WG. Emerging role of innate immunity in organ transplantation. Part I: Evolution of innate immunity and oxidative allograft injury. Transplant Rev 2012; 26: 60–72.
CITATION Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, et al. Mitochondrial DNA that escapes from autophagy causes infammation and heart failure. Nature 2012; 485: 251–255.
CITATION Rosin DL, Okusa MD. Dangers within: DAMP responses to damage and cell death in kidney disease. J Am Soc Nephrol 2011; 22: 416–425.
CITATION Zhang J-G, Czabotar PE, Policheni AN, Caminschi I, Wan SS, Kitsoulis S, et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin flaments. Immunity 2012; 36: 646–657.
SUMMARY AND ANALYSIS
Infection is detected through binding of conserved pathogen-associated molecular patterns (PAMPs) to pattern recognition receptors (PRRs) expressed on leukocytes and other cells. PAMP ligation of PRR transduces intracellular signaling pathways that initiate the innate immune response necessary for the host to deal with the pathogen. As one example of a PAMP-PRR pair, bacterial DNA contains unmethylated CpG motifs, not found in the genomic DNA of animals, and is a ligand for intracellular toll-like receptor 9 (TLR9). CpG binding to TLR9 stimulates cells to produce the acute-phase cytokines interleukin (IL)-1β, IL-6 and TNFα that trigger innate immunity.
This is all well and good for dealing with microbial infections, but how does the animal detect the presence of “sterile infammation,” such as that imposed by surgical trauma or ischemia reperfusion injury? During such tissue inflammation, cell injury or death results in the release or generation of molecules that are endogenous PRR ligands; in a manner similar to that of PAMPs, binding of these danger-associated molecular patterns (DAMPs) stimulates cells to produce acute-phase cytokines and express other infammatory functions (Rosin et al.). Such DAMPs include heparin sulfate, fragments of hyaluronin and fbrinogen, all components of the extracellular matrix, and high-mobility group protein B1. Obviously it is important to identify other molecules generated by injured mammalian cells that activate PRR to initiate infammation in various pathologies including graft injury.
Unlike animal genomic DNA, mitochondrial DNA does contain unmethylated CpG motifs, likely refecting the bacterial origin of these energy-generating organelles. During myocardial stress, damaged mitochondria are engulfed and degraded by the lysosomal/autophagy system within cardiac myocytes, including DNase II-mediated degradation of mitochondrial DNA. In a mouse model of hemodynamic stress imposed by thoracic transverse aortic constriction, Oka et al. report that any mitochondrial DNA escaping this degradation binds to TLR9, inducing cardiomyocytes to produce IL-1β and IL-6, which initiate myocarditis and dilated cardiomyopathy. Whereas deletion of the DNase II gene had no apparent effect on the health of unperturbed mice, imposition of hemodynamic stress in DNase II-deficient animals resulted in a severe and lethal myocarditis. This pathology was dependent on the expression of TLR9 and was blocked by treating the knockout mice with an inhibitory oligonucleotide, which binds to but does not activate TLR9, immediately prior to and following imposition of the hemodynamic stress.
The dendritic cell receptor DNGR-1 is a C-type lectin PRR that had been identifed on a population of dendritic cells (DCs) involved in cross-presentation of antigens exposed by necrotic cells. DNGR-1 binds to a previously unidentifed ligand exposed on necrotic cells, and this binding activates DC cross-presentation pathways required for the priming of cytotoxic T cell responses to antigens of the necrotic cells. In a series of biochemical studies, two groups of investigators used soluble DNGR-1 constructs to interrogate intracellular and membrane expressed proteins of necrotic cells and identifed F-actin from the polymerized actin cytoskeleton as the DAMP directing DC binding to necrotic cells and the activation of DC cross-presentation of necrotic cell antigens (Ahrens et al., Zhang et al.).
Overall, these elegant studies expose two novel intracellular DAMPs that are generated during cell injury and bind to intracellular or cell membrane expressed PRRs to initiate infammatory responses. Of interest to transplant investigators is the mitochondrial damage and cell necrosis initiated during reperfusion of ischemic tissues (Land). It is conceivable (and worth investigating) that ischemia-reperfusion injury, as well as acute and chronic cell or antibody-mediated graft injury, could provoke the generation of mitochondrial DNA leading to acute-phase cytokine production and F-actin fragments that activate DCs to prime alloreactive CD8 T cell responses.
Dr. Fairchild is with the Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Bromberg is director of the Division of Transplantation, University of Maryland School of Medicine, Baltimore.
[ DNA Inflames the Heart. Pressure overload of cardiomyocytes damages mitochondria, resulting in lysosomal degredation and release of unmethylated CpG DNA, which stimulate TLR and cytokine production. ]