The concept that sepsis is the result of an uncontrolled inflammatory response of the host’s innate immune system towards invading pathogens has recently been challenged. Evidence is accumulating that, in addition, host-derived alarm molecules are released during sepsis- and trauma-associated cell death, thus triggering the host’s immune response. The identification and characterization of exogenous as well as endogenous danger molecules allowed significant advances in our understanding of the pathophysiology of sepsis and may provide potential targets for therapeutic interventions.

Keywords:
Damage-associated molecular patterns, Pathogen-associated molecular patterns, Alarmins, Sepsis, Complement
1.
Tan SY, Dee MK: Elie Metchnikoff (1845–1916): discoverer of phagocytosis. Singapore Med J 2009;50:456–457.
2.
Hansen JD, Vojtech LN, Laing KJ: Sensing disease and danger: a survey of vertebrate PRRs and their origins. Dev Comp Immunol 2011;35:886–897.
3.
Janeway CA Jr: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54:1–13.
4.
Seong SY, Matzinger P: Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 2004;4:469–478.
5.
Oppenheim JJ, Yang D: Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 2005;17:359–365.
6.
Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546–1554.
7.
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–874.
8.
Angus DC, Burgner D, Wunderink R, Mira JP, Gerlach H, Wiedermann CJ, Vincent JL: The PIRO concept: P is for predisposition. Crit Care 2003;7:248–251.
9.
Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008;8:776–787.
10.
Tracey KJ: Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289–296.
11.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–1377.
12.
Henneke P, Golenbock DT: Innate immune recognition of lipopolysaccharide by endothelial cells. Crit Care Med 2002;30:S207–S213.
13.
Kox WJ, Volk T, Kox SN, Volk HD: Immunomodulatory therapies in sepsis. Intensive Care Med 2000;26(suppl 1):S124–S128.
14.
Muenzer JT, Davis CG, Chang K, Schmidt RE, Dunne WM, Coopersmith CM, Hotchkiss RS: Characterization and modulation of the immunosuppressive phase of sepsis. Infect Immun 2010;78:1582–1592.
15.
Terregino CA, Lopez BL, Karras DJ, Killian AJ, Arnold GK: Endogenous mediators in emergency department patients with presumed sepsis: are levels associated with progression to severe sepsis and death? Ann Emerg Med 2000;35:26–34.
16.
Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H: Role of Toll-like receptors in the development of sepsis. Shock 2008;29:315–321.
17.
Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 2006;124:783–801.
18.
Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099–1103.
19.
Mattsson E, Rollof J, Verhoef J, Van DH, Fleer A: Serum-induced potentiation of tumor necrosis factor alpha production by human monocytes in response to staphylococcal peptidoglycan: involvement of different serum factors. Infect Immun 1994;62:3837–3843.
20.
Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nunez G, Inohara N: An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 2003;4:702–707.
21.
Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S: A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–745.
22.
Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ: Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999;274:17406–17409.
23.
Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC: Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 2007;25:713–724.
24.
Roeder A, Kirschning CJ, Rupec RA, Schaller M, Korting HC: Toll-like receptors and innate antifungal responses. Trends Microbiol 2004;12:44–49.
25.
Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, Aderem A: The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 1999;401:811–815.
26.
Mogensen TH, Paludan SR: Reading the viral signature by Toll-like receptors and other pattern recognition receptors. J Mol Med (Berl) 2005;83:180–192.
27.
Kato H, Takahasi K, Fujita T: RIG-I-like receptors: cytoplasmic sensors for non-self RNA. Immunol Rev 2011;243:91–98.
28.
Hefeneider SH, Cornell KA, Brown LE, Bakke AC, McCoy SL, Bennett RM: Nucleosomes and DNA bind to specific cell-surface molecules on murine cells and induce cytokine production. Clin Immunol Immunopathol 1992;63:245–251.
29.
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002;416:603–607.
30.
Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, Taniguchi T: DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 2007;448:501–505.
31.
Saukkonen K, Lakkisto P, Pettila V, Varpula M, Karlsson S, Ruokonen E, Pulkki K: Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock. Clin Chem 2008;54:1000–1007.
32.
Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT: Extracellular histones are major mediators of death in sepsis. Nat Med 2009;15:1318–1321.
33.
Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P: Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007;13:463–469.
34.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–1535.
35.
Chaput C, Zychlinsky A: Sepsis: the dark side of histones. Nat Med 2009;15:1245–1246.
36.
Frehlick LJ, Eirin-Lopez JM, Ausio J: New insights into the nucleophosmin/nucleoplasmin family of nuclear chaperones. Bioessays 2007;29:49–59.
37.
Kerr LE, Birse-Archbold JL, Short DM, McGregor AL, Heron I, Macdonald DC, Thompson J, Carlson GJ, Kelly JS, McCulloch J, Sharkey J: Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death. Oncogene 2007;26:2554–2562.
38.
Nawa Y, Kawahara K, Tancharoen S, Meng X, Sameshima H, Ito T, Masuda Y, Imaizumi H, Hashiguchi T, Maruyama I: Nucleophosmin may act as an alarmin: implications for severe sepsis. J Leukoc Biol 2009;86:645–653.
39.
Andersson U, Erlandsson-Harris H, Yang H, Tracey KJ: HMGB1 as a DNA-binding cytokine. J Leukoc Biol 2002;72:1084–1091.
40.
Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999;285:248–251.
41.
Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, Dumitriu IE, Muller S, Iannacone M, Traversari C, Bianchi ME, Manfredi AA: HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 2004;5:825–830.
42.
Zurolo E, Iyer A, Maroso M, Carbonell C, Anink JJ, Ravizza T, Fluiter K, Spliet WG, van Rijen PC, Vezzani A, Aronica E: Activation of Toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development. Brain 2011;134:1015–1032.
43.
Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AF: Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 2003;101:2652–2660.
44.
Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ: HMG-1 as a mediator of acute lung inflammation. J Immunol 2000;165:2950–2954.
45.
Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Wang H, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ: Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004;101:296–301.
46.
Wang H, Yang H, Tracey KJ: Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med 2004;255:320–331.
47.
Gray MW, Burger G, Lang BF: Mitochondrial evolution. Science 1999;283:1476–1481.
48.
Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P: Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 2011;32:157–164.
49.
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ: Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010;464:104–107.
50.
Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A: Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol 2004;75:995–1000.
51.
Raoof M, Zhang Q, Itagaki K, Hauser CJ: Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J Trauma 2010;68:1328–1332.
52.
Willart MA, Lambrecht BN: The danger within: endogenous danger signals, atopy and asthma. Clin Exp Allergy 2009;39:12–19.
53.
Novak I: ATP as a signaling molecule: the exocrine focus. News Physiol Sci 2003;18:12–17.
54.
Martinon F: Detection of immune danger signals by NALP3. J Leukoc Biol 2008;83:507–511.
55.
Dinarello CA: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res 2004;10:201–222.
56.
Decker T: Sepsis: avoiding its deadly toll. J Clin Invest 2004;113:1387–1389.
57.
Kohl J: The role of complement in danger sensing and transmission. Immunol Res 2006;34:157–176.
58.
Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J: The role of the anaphylatoxins in health and disease. Mol Immunol 2009;46:2753–2766.
59.
Flierl MA, Rittirsch D, Nadeau BA, Day DE, Zetoune FS, Sarma JV, Huber-Lang MS, Ward PA: Functions of the complement components C3 and C5 during sepsis. FASEB J 2008;22:3483–3490.
60.
Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Kohl J, Gerard C, Sarma JV, Ward PA: Functional roles for C5a receptors in sepsis. Nat Med 2008;14:551–557.
61.
Nakae H, Endo S, Inada K, Takakuwa T, Kasai T, Yoshida M: Serum complement levels and severity of sepsis. Res Commun Chem Pathol Pharmacol 1994;84:189–195.
62.
Ward PA: The dark side of C5a in sepsis. Nat Rev Immunol 2004;4:133–142.
63.
Hajishengallis G, Lambris JD: Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol 2010;31:154–163.
64.
Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Bruckner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M: Molecular intercommunication between the complement and coagulation systems. J Immunol 2010;185:5628–5636.
65.
Zhang X, Kimura Y, Fang C, Zhou L, Sfyroera G, Lambris JD, Wetsel RA, Miwa T, Song WC: Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo. Blood 2007;110:228–236.
66.
Kaczorowski DJ, Afrazi A, Scott MJ, Kwak JH, Gill R, Edmonds RD, Liu Y, Fan J, Billiar TR: Pivotal advance: the pattern recognition receptor ligands lipopolysaccharide and polyinosine-polycytidylic acid stimulate factor B synthesis by the macrophage through distinct but overlapping mechanisms. J Leukoc Biol 2010;88:609–618.
67.
Levi M, Ten CH: Disseminated intravascular coagulation. N Engl J Med 1999;341:586–592.
68.
Abraham E: Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol 2000;22:401–404.
69.
Lissauer ME, Johnson SB, Siuzdak G, Bochicchio G, Whiteford C, Nussbaumer B, Moore R, Scalea TM: Coagulation and complement protein differences between septic and uninfected systemic inflammatory response syndrome patients. J Trauma 2007;62:1082–1092.
70.
Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P, Rafail S, Kartalis G, Sideras P, Lambris JD: A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 2006;177:4794–4802.
71.
Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD: Complement and coagulation: strangers or partners in crime? Trends Immunol 2007;28:184–192.
72.
Krarup A, Wallis R, Presanis JS, Gal P, Sim RB: Simultaneous activation of complement and coagulation by MBL-associated serine protease 2. PLoS One 2007;2:e623.
73.
Ghebrehiwet B, Silverberg M, Kaplan AP: Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med 1981;153:665–676.
74.
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA: Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006;12:682–687.
75.
Perl M, Denk S, Kalbitz M, Huber-Lang M: Granzyme B: a new crossroad of complement and apoptosis. Adv Exp Med Biol 2012;946:135–146.
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