Damage associated molecular pattern molecule
Damage associated molecular pattern molecules [DAMPs] derived molecules can initiate and perpetuate
immune responsein the noninfectious inflammatory response. They serve as the “Signal 0” similar to pathogenassociated molecular pattern molecules [PAMPs] that drive initiation and perpetuation of the inflammatory response. [ [Janeway C. Immunogenicity signals 1,2,3 and 0. "Immunol Today" 1989; 10(9):283-6.] ] Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that, when released outside the cell following tissue injury, move from a reducing to an oxidizing milieu resulting in their functional denaturation [ [Rubartelli, A. and Michael T. Lotze (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends in Immunology 28, 429-436.] ] . Also, following necrosis(a kind of cell death), tumor DNA is released into the extranuclear space/extracellular micro-environment and functions as a DAMP [ [Farkas, Adam M.; Tina M. Kilgore, and Michael T. Lotze (2007) Detecting DNA: getting and begetting cancer. Current Opinion in Investigational Drugs 8, 981-986.] ] .
Two papers appearing in the same year presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first [ [Land,Walter; Helmut Schneeberger, Stefan Schleibner, Wolf-Dieter Illner, Dietmar Abendroth, G. Rutili, Karl-E. Arfors, Konrad Messmer (1994) The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 57(2):211-7.] ] came from transplant surgeons who conducted a prospective randomized double-blind placebo-controlled trial. Administration of recombinant human
superoxide dismutatase(rh-SOD) in recipients of cadaveric renal allografts demonstrated prolonged patient and graft survival with improvement in both acute and chronic rejection events. They speculated that the effect was related to its antioxidantaction on the initial ischemia/reperfusion injury of the renal allograft, thereby reducing the immunogenicityof the allograft and the “grateful dead” or stressed cells. Thus free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses. The second [ [Matzinger, Polly (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12,991-1045.] ] , suggested the possibility that the immune system detected “danger”, through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. Thus these two papers together presaged the modern sense of the role of DAMPs and redox reviewed here, important apparently for both plant and animal resistance to pathogens and the response to cellular injury or damage.
Examples of DAMPs
DAMPs vary greatly depending on the type of cell (epithelial or mesenchymal) and injured tissue. Protein DAMPs include intracellular proteins, such as hear-shock proteins [ [Gabriel, S. Panayi; Valerie M. Corrigall and Brian Henderson (2004) Stress cytokines: pivotal proteins in immune regulatory networks. Current Opinion in Immunology 16, 531-534.] ] or HMGB1 [ [Scaffidi, Paola; T. Misteli, and Marco E. Bianchi (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195.] ] (high-mobility group box 1), and proteins derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments [ [Kara, Scheibner A.; Michael A. Lutz, Sada Boodoo, Matthew J. Fenton, Jonathan D. Powell and Maureen R. Horton (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272-1281.] ] . Examples of non-protein DAMPs include ATP [ [Boeynaems, Jean M. and Communi, D. (2006) Modulation of inflammation by extracellular nucleotides. J. Invest. Dermatol. 126, 943-944.] ] [ [Bours, Martijn J.; Swennen EL, Di Virgilio F, Cronstein B. N. and Dagnelie PC (2006) Adenosine 5’-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358-404.] ] , uric acid [ [Shi, Y., James E. Evans and Kenneth L. Rock (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516-521.] ] , heparin sulfate and DNA [ [Farkas, Adam M.; Tina M. Kilgore, and Michael T. Lotze (2007) Detecting DNA: getting and begetting cancer. Current Opinion in Investigational Drugs 8, 981-986.] ] .
chromatin-associated protein high-mobility group box 1 (HMGB1) is a prototypical leaderless secreted protein [LSP] secreted by hematopoietic cells through a lysosome-mediated pathway [ [Gardella, Stefania.; Cristina Andrei, Denise Ferrera, Lavinia V. Lotti, Maria R. Torrisi, Marco E. Bianchi, and Anna Rubartelli. (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 3, 995-1001] ] . It is a major mediator of endotoxinshock [ [Wang, Haichao.; Ona Bloom, Minghuang Zhang, Jaideep M. Vishnubhakat, Michael Ombrellino, Jiantu Che, Asia Frazier, Huan Yang, Svetlana Ivanova, Lyudmila Borovikova, Kirk R.Manogue, Eugen Faist, Edward Abraham, Jan Andersson, Ulf Andersson, Patricia E. Molina, Naji N. Abumrad, Andrew Sama, Kevin J. Tracey (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248-251] ] and acts on several immune cells to trigger inflammatory responses as a DAMP [ [Scaffidi, Paola; T. Misteli, and Marco E. Bianchi (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195.] ] . Known receptors for HMGB1 include TLR2, TLR4 and RAGE (Receptor for Advanced Glycation Endproducts). [http://en.wikipedia.org/wiki/HMGB1] HMGB1 can induce Dendritic Cell Maturation via upregulation of CD80, CD83, CD86 and CD11c, induce production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8) as well as upregulate expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells.
The presence of
DNAanywhere other than the nucleus or mitochondriais perceived as a DAMP and triggers responses mediated by TLR9and DAIthat drive cellular activation and immunoreactivity. Interestingly, some tissues such as the gut are inhibited by DNA in their immune response.
S100 is a multigenic family of calcium modulated proteins involved in intracellular and extracellular regulatory activities with a connection to cancer as well as tissue, particularly neuronal, injury [ [Diederichs Sven; Etmar Bulk, Björn Steffen, Ping Ji, Lara Tickenbrock, Kerstin Lang, Kurt S. Zänker, Ralf Metzger, Paul M. Schneider, Volker Gerke, Michael Thomas, Wolfgang E. Berdel, Hubert Serve and Carsten Müller-Tidow. (2004) S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer. Cancer Res. 64, 5564-5569] ] [ [Emberley, Ethan D., Leigh C. Murphy and Peter H. Watson (2004) S100A7 and the progression of breast cancer. Breast Cancer Res. 6, 153-159] ] [ [Emberley, Ethan D., Leigh C. Murphy and Peter H. Watson (2004) S100 proteins and their influence on pro-survival pathways in cancer. Biochem Cell Biol. 82, 508–515.] ] [ [Lin, Jing; Qingyuan Yang, Zhe Yan, Joseph Markowitz, Paul T. Wilder, France Carrier, and David J. Weber (2004) Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J Biol Chem. 279, 34071–34077.] ] [ [Marenholz, Ingo, Claus W. Heizmann, and Günter Fritz (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun. 322, 1111–1122.] ] .
Purine Metabolites [ATP, adenosine, uric acid]
Nucleotides (such as ATP) and nucleosides (such as adenosine) that have reached the extracellular space can also serve as ‘‘danger’’signals [ [la Sala, Andrea; Davide Ferrari, Francesco Di Virgilio, Marco Idzko, Johannes Norgauer and Giampiero Girolomoni (2003) Alerting and tuning the immune response by extracellular nucleotides. J Leukoc Biol. 73, 339–343.] ] . ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death [ [Zeh, Herbert J. III, and Michael T. Lotze (2005) Addicted to death: invasive cancer and the immune response to unscheduled cell death. J. Immunother. 28, 1–9.] ] . The immunobiology of these molecules once released into the extracellular milieu is complex. At lower concentrations, extracellular ATP serves as a chemoattractant for immature DCs as well as a maturation signal to upregulate co-stimulatory molecules. At higher concentrations, ATP blocks the synthesis of pro-inflammatory cytokines[ [la Sala, Andrea; Silvia Sebastiani, Davide Ferrari, Francesco Di Virgilio, Marco Idzko, Johannes Norgauer, and Giampiero Girolomoni (2002) Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood. 99, 1715–1722.] ] [ [la Sala, Andrea; Davide Ferrari, Silvia Corinti, Andrea Cavani, Francesco Di Virgilio and Giampiero Girolomoni (2001) Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J Immunol. 166,1611–1617.] ] [ [Haskó, György; David G. Kuhel, Andrew L. Salzman, and Csaba Szabó (2000) ATP suppression of interleukin-12 and tumour necrosis factor- α release from macrophages. Br J Pharmacol. 129, 909–914.] ] . Similarly, adenosine has dual effects on the function of the plasmacytoid DC. Uric acidis also an endogenous danger signal released by injured cells [ [Schnurr, Max; Tracey Toy, Amanda Shin, Gunther Hartmann, Simon Rothenfusser, Julia Soellner, Ian D. Davis, Jonathan Cebon, Eugene Maraskovsky (2004) Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood. 103, 1391–1397.] ] .
Clinical Targets in Various Disorders
[arthritis, cancer, ischemia-reperfusion, myocardial infarction, stroke] The application of therapeutics in this area could imaginatively include: 1] preventing DAMP release [proapoptotic therapies; platinums; ethyl pyruvate] ; 2] neutralizing or blocking DAMPs extracellularly [anti-HMGB1; rasburicase; sRAGE, etc.] ; and 3] blocking the DAMP receptors or their signaling [RAGE small molecule antagonists; TLR4 antagonists; antibodies to DAMP-R.
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