Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets
Andreas Barratt-Due, Søren Erik Pischke, Per H Nilsson, Terje Espevik, Tom Eirik Mollnes, Andreas Barratt-Due, Søren Erik Pischke, Per H Nilsson, Terje Espevik, Tom Eirik Mollnes
Abstract
The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by "dual blockade" of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.
Keywords: inflammation; innate immunity; therapy.
© The Author(s).
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References
- Thaiss C. A., Levy M., Itav S., Elinav E. (2016) Integration of innate immune signaling. Trends Immunol. 37, 84–101.
- Matzinger P. (1994) Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045.
- Inflammation and Host Response to Injury Large-Scale Collaborative Research Program (2011) A genomic storm in critically injured humans. J. Exp. Med. 208, 2581–2590.
- Sendide K., Reiner N. E., Lee J. S., Bourgoin S., Talal A., Hmama Z. (2005) Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1. J. Immunol. 174, 4210–4219.
- Köhl J. (2006) The role of complement in danger sensing and transmission. Immunol. Res. 34, 157–176.
- Hajishengallis G., Lambris J. D. (2010) Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154–163.
- Song W. C. (2012) Crosstalk between complement and Toll-like receptors. Toxicol. Pathol. 40, 174–182.
- Mollnes T. E., Christiansen D., Brekke O. L., Espevik T. (2008) Hypothesis: combined inhibition of complement and CD14 as treatment regimen to attenuate the inflammatory response. Adv. Exp. Med. Biol. 632, 253–263.
- Berends E. T., Gorham R. D. Jr.,Ruyken M., Soppe J. A., Orhan H., Aerts P. C., de Haas C. J., Gros P., Rooijakkers S. H. (2015) Molecular insights into the surface-specific arrangement of complement C5 convertase enzymes. BMC Biol. 13, 93.
- Hobart M. (1984) Agreement now the norm. Immunol. Today 5, 121–125.
- Bajic G., Degn S. E., Thiel S., Andersen G. R. (2015) Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J. 34, 2735–2757.
- Atkinson J. P., Farries T. (1987) Separation of self from non-self in the complement system. Immunol. Today 8, 212–215.
- Barratt-Due A., Pischke S. E., Brekke O. L., Thorgersen E. B., Nielsen E. W., Espevik T., Huber-Lang M., Mollnes T. E. (2012) Bride and groom in systemic inflammation—the bells ring for complement and Toll in cooperation. Immunobiology 217, 1047–1056.
- Ward P. A. (2004) The dark side of C5a in sepsis. Nat. Rev. Immunol. 4, 133–142.
- Müller-Eberhard H. J. (1988) Molecular organization and function of the complement system. Annu. Rev. Biochem. 57, 321–347.
- Morgan B. P. (1989) Complement membrane attack on nucleated cells: resistance, recovery and non-lethal effects. Biochem. J. 264, 1–14.
- Rother R. P., Rollins S. A., Mojcik C. F., Brodsky R. A., Bell L. (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256–1264.
- Licht C., Greenbaum L. A., Muus P., Babu S., Bedrosian C. L., Cohen D. J., Delmas Y., Douglas K., Furman R. R., Gaber O. A., Goodship T., Herthelius M., Hourmant M., Legendre C. M., Remuzzi G., Sheerin N., Trivelli A., Loirat C. (2015) Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 87, 1061–1073.
- Ricklin D., Lambris J. D. (2013) Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190, 3839–3847.
- Morgan B. P., Harris C. L. (2015) Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877.
- Mollnes T. E., Kirschfink M. (2006) Strategies of therapeutic complement inhibition. Mol. Immunol. 43, 107–121.
- Delmas Y., Vendrely B., Clouzeau B., Bachir H., Bui H. N., Lacraz A., Hélou S., Bordes C., Reffet A., Llanas B., Skopinski S., Rolland P., Gruson D., Combe C. (2014) Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol. Dial. Transplant. 29, 565–572.
- Shi J., Rose E. L., Singh A., Hussain S., Stagliano N. E., Parry G. C., Panicker S. (2014) TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood 123, 4015–4022.
- Levy M., Mealy M. A. (2014) Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica. Neurol. Neuroimmunol. Neuroinflamm. 1, e5.
- Igonin A. A., Protsenko D. N., Galstyan G. M., Vlasenko A. V., Khachatryan N. N., Nekhaev I. V., Shlyapnikov S. A., Lazareva N. B., Herscu P. (2012) C1-esterase inhibitor infusion increases survival rates for patients with sepsis. Crit. Care Med. 40, 770–777.
- Ziccardi R. J. (1982) A new role for C-1-inhibitor in homeostasis: control of activation of the first component of human complement. J. Immunol. 128, 2505–2508.
- Nielsen E. W., Waage C., Fure H., Brekke O. L., Sfyroera G., Lambris J. D., Mollnes T. E. (2007) Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement. Mol. Immunol. 44, 1819–1826.
- Mastellos D. C., Yancopoulou D., Kokkinos P., Huber-Lang M., Hajishengallis G., Biglarnia A. R., Lupu F., Nilsson B., Risitano A. M., Ricklin D., Lambris J. D. (2015) Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur. J. Clin. Invest. 45, 423–440.
- Phase Ia Investigators (2014) A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy. Retina 34, 313–320.
- Zhang Y., Nester C. M., Holanda D. G., Marsh H. C., Hammond R. A., Thomas L. J., Meyer N. C., Hunsicker L. G., Sethi S., Smith R. J. (2013) Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J. Am. Soc. Nephrol. 24, 1820–1829.
- Nunn M. A., Sharma A., Paesen G. C., Adamson S., Lissina O., Willis A. C., Nuttall P. A. (2005) Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J. Immunol. 174, 2084–2091.
- Roversi P., Lissina O., Johnson S., Ahmat N., Paesen G. C., Ploss K., Boland W., Nunn M. A., Lea S. M. (2007) The structure of OMCI, a novel lipocalin inhibitor of the complement system. J. Mol. Biol. 369, 784–793.
- Ward P. A. (2009) Functions of C5a receptors. J. Mol. Med. 87, 375–378.
- Woodruff T. M., Nandakumar K. S., Tedesco F. (2011) Inhibiting the C5-C5a receptor axis. Mol. Immunol. 48, 1631–1642.
- MG Study Group (2013) A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 48, 76–84.
- De Fontbrune F. S., Galambrun C., Sirvent A., Huynh A., Faguer S., Nguyen S., Bay J. O., Neven B., Moussi J., Simon L., Xhaard A., Resche-Riggon M., O’Meara A., Fremeaux-Bacchi V., Veyradier A., Socié G., Coppo P., de Latour R. P. (2015) Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation 99, 1953–1959.
- Pierangeli S. S., Chen P. P., Raschi E., Scurati S., Grossi C., Borghi M. O., Palomo I., Harris E. N., Meroni P. L. (2008) Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin. Thromb. Hemost. 34, 236–250.
- Asavapanumas N., Ratelade J., Papadopoulos M. C., Bennett J. L., Levin M. H., Verkman A. S. (2014) Experimental mouse model of optic neuritis with inflammatory demyelination produced by passive transfer of neuromyelitis optica-immunoglobulin G. J. Neuroinflammation 11, 16.
- Le Quintrec M., Zuber J., Moulin B., Kamar N., Jablonski M., Lionet A., Chatelet V., Mousson C., Mourad G., Bridoux F., Cassuto E., Loirat C., Rondeau E., Delahousse M., Frémeaux-Bacchi V. (2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am. J. Transplant. 13, 663–675.
- Savva A., Roger T. (2013) Targeting Toll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases. Front. Immunol. 4, 387.
- Schaefer L. (2014) Complexity of danger: the diverse nature of damage-associated molecular patterns. J. Biol. Chem. 289, 35237–35245.
- Zanoni I., Ostuni R., Marek L. R., Barresi S., Barbalat R., Barton G. M., Granucci F., Kagan J. C. (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868–880.
- Husebye H., Aune M. H., Stenvik J., Samstad E., Skjeldal F., Halaas O., Nilsen N. J., Stenmark H., Latz E., Lien E., Mollnes T. E., Bakke O., Espevik T. (2010) The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity 33, 583–596.
- Park B. S., Song D. H., Kim H. M., Choi B. S., Lee H., Lee J. O. (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195.
- Latz E., Visintin A., Lien E., Fitzgerald K. A., Monks B. G., Kurt-Jones E. A., Golenbock D. T., Espevik T. (2002) Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the Toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J. Biol. Chem. 277, 47834–47843.
- Lee C. C., Avalos A. M., Ploegh H. L. (2012) Accessory molecules for Toll-like receptors and their function. Nat. Rev. Immunol. 12, 168–179.
- Nilsen N. J., Deininger S., Nonstad U., Skjeldal F., Husebye H., Rodionov D., von Aulock S., Hartung T., Lien E., Bakke O., Espevik T. (2008) Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling: role of CD14 and CD36. J. Leukoc. Biol. 84, 280–291.
- Di Gioia M., Zanoni I. (2015) Toll-like receptor co-receptors as master regulators of the immune response. Mol. Immunol. 63, 143–152.
- Dagvadorj J., Shimada K., Chen S., Jones H. D., Tumurkhuu G., Zhang W., Wawrowsky K. A., Crother T. R., Arditi M. (2015) Lipopolysaccharide induces alveolar macrophage necrosis via CD14 and the P2X7 receptor leading to interleukin-1alpha release. Immunity 42, 640–653.
- Patel M. C., Shirey K. A., Pletneva L. M., Boukhvalova M. S., Garzino-Demo A., Vogel S. N., Blanco J. C. (2014) Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol. 9, 811–829.
- Arumugam T. V., Okun E., Tang S. C., Thundyil J., Taylor S. M., Woodruff T. M. (2009) Toll-like receptors in ischemia-reperfusion injury. Shock 32, 4–16.
- Farrar C. A., Keogh B., McCormack W., O’Shaughnessy A., Parker A., Reilly M., Sacks S. H. (2012) Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia-reperfusion injury. FASEB J. 26, 799–807.
- Arslan F., Houtgraaf J. H., Keogh B., Kazemi K., de Jong R., McCormack W. J., O’Neill L. A., McGuirk P., Timmers L., Smeets M. B., Akeroyd L., Reilly M., Pasterkamp G., de Kleijn D. P. (2012) Treatment with OPN-305, a humanized anti-Toll-Like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs. Circ. Cardiovasc. Interv. 5, 279–287.
- Reilly M., Miller R. M., Thomson M. H., Patris V., Ryle P., McLoughlin L., Mutch P., Gilboy P., Miller C., Broekema M., Keogh B., McCormack W., van de Wetering de Rooij J. (2013) Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody. Clin. Pharmacol. Ther. 94, 593–600.
- Matsunaga N., Tsuchimori N., Matsumoto T., Ii M. (2011) TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol. Pharmacol. 79, 34–41.
- Kuno M., Nemoto K., Ninomiya N., Inagaki E., Kubota M., Matsumoto T., Yokota H. (2009) The novel selective Toll-like receptor 4 signal transduction inhibitor TAK-242 prevents endotoxaemia in conscious Guinea-pigs. Clin. Exp. Pharmacol. Physiol. 36, 589–593.
- Fenhammar J., Rundgren M., Forestier J., Kalman S., Eriksson S., Frithiof R. (2011) Toll-like receptor 4 inhibitor TAK-242 attenuates acute kidney injury in endotoxemic sheep. Anesthesiology 114, 1130–1137.
- Fenhammar J., Rundgren M., Hultenby K., Forestier J., Taavo M., Kenne E., Weitzberg E., Eriksson S., Ozenci V., Wernerson A., Frithiof R. (2014) Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep. Crit. Care 18, 488.
- Rice T. W., Wheeler A. P., Bernard G. R., Vincent J. L., Angus D. C., Aikawa N., Demeyer I., Sainati S., Amlot N., Cao C., Ii M., Matsuda H., Mouri K., Cohen J. (2010) A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685–1694.
- Mullarkey M., Rose J. R., Bristol J., Kawata T., Kimura A., Kobayashi S., Przetak M., Chow J., Gusovsky F., Christ W. J., Rossignol D. P. (2003) Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J. Pharmacol. Exp. Ther. 304, 1093–1102.
- Lynn M., Rossignol D. P., Wheeler J. L., Kao R. J., Perdomo C. A., Noveck R., Vargas R., D’Angelo T., Gotzkowsky S., McMahon F. G. (2003) Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J. Infect. Dis. 187, 631–639.
- ACCESS Study Group (2013) Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154–1162.
- Shirey K. A., Lai W., Scott A. J., Lipsky M., Mistry P., Pletneva L. M., Karp C. L., McAlees J., Gioannini T. L., Weiss J., Chen W. H., Ernst R. K., Rossignol D. P., Gusovsky F., Blanco J. C., Vogel S. N. (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497, 498–502.
- Gustavsen A., Nymo S., Landsem A., Christiansen D., Ryan L., Husebye H., Lau C., Pischke S. E., Lambris J. D., Espevik T., Mollnes T. E. (2016) Combined inhibition of complement and CD14 attenuates bacteria-induced inflammation in human whole blood more efficiently than antagonizing the Toll-like receptor 4-MD2 complex. J. Infect. Dis. 214, 140–150.
- Thorgersen E. B., Hellerud B. C., Nielsen E. W., Barratt-Due A., Fure H., Lindstad J. K., Pharo A., Fosse E., Tønnessen T. I., Johansen H. T., Castellheim A., Mollnes T. E. (2010) CD14 inhibition efficiently attenuates early inflammatory and hemostatic responses in Escherichia coli sepsis in pigs. FASEB J. 24, 712–722.
- Thorgersen E. B., Pischke S. E., Barratt-Due A., Fure H., Lindstad J. K., Pharo A., Hellerud B. C., Mollnes T. E. (2013) Systemic CD14 inhibition attenuates organ inflammation in porcine Escherichia coli sepsis. Infect. Immun. 81, 3173–3181.
- Olszyna D. P., Verbon A., Pribble J. P., Turner T., Axtelle T., van Deventer S. J., van der Poll T. (2003) Effect of IC14, an anti-CD14 antibody, on plasma and cell-associated chemokines during human endotoxemia. Eur. Cytokine Netw. 14, 158–162.
- Spek C. A., Verbon A., Aberson H., Pribble J. P., McElgunn C. J., Turner T., Axtelle T., Schouten J., Van Der Poll T., Reitsma P. H. (2003) Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo. J. Clin. Immunol. 23, 132–140.
- Verbon A., Meijers J. C., Spek C. A., Hack C. E., Pribble J. P., Turner T., Dekkers P. E., Axtelle T., Levi M., van Deventer S. J., Reitsma P. H., van der Poll T. (2003) Effects of IC14, an anti-CD14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans. J. Infect. Dis. 187, 55–61.
- Reinhart K., Glück T., Ligtenberg J., Tschaikowsky K., Bruining A., Bakker J., Opal S., Moldawer L. L., Axtelle T., Turner T., Souza S., Pribble J. (2004) CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14). Crit. Care Med. 32, 1100–1108.
- Lau C., Gunnarsen K. S., Høydahl L. S., Andersen J. T., Berntzen G., Pharo A., Lindstad J. K., Ludviksen J. K., Brekke O. L., Barratt-Due A., Nielsen E. W., Stokes C. R., Espevik T., Sandlie I., Mollnes T. E. (2013) Chimeric anti-CD14 IGG2/4 hybrid antibodies for therapeutic intervention in pig and human models of inflammation. J. Immunol. 191, 4769–4777.
- Mollnes T. E., Brekke O. L., Fung M., Fure H., Christiansen D., Bergseth G., Videm V., Lappegård K. T., Köhl J., Lambris J. D. (2002) Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100, 1869–1877.
- Lappegård K. T., Christiansen D., Pharo A., Thorgersen E. B., Hellerud B. C., Lindstad J., Nielsen E. W., Bergseth G., Fadnes D., Abrahamsen T. G., Høiby E. A., Schejbel L., Garred P., Lambris J. D., Harboe M., Mollnes T. E. (2009) Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. Proc. Natl. Acad. Sci. USA 106, 15861–15866.
- Brekke O. L., Christiansen D., Fure H., Fung M., Mollnes T. E. (2007) The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood. J. Leukoc. Biol. 81, 1404–1413.
- Brekke O. L., Christiansen D., Fure H., Pharo A., Fung M., Riesenfeld J., Mollnes T. E. (2008) Combined inhibition of complement and CD14 abolish E. coli-induced cytokine-, chemokine- and growth factor-synthesis in human whole blood. Mol. Immunol. 45, 3804–3813.
- Hellerud B. C., Stenvik J., Espevik T., Lambris J. D., Mollnes T. E., Brandtzaeg P. (2008) Stages of meningococcal sepsis simulated in vitro, with emphasis on complement and Toll-like receptor activation. Infect. Immun. 76, 4183–4189.
- Lau C., Nygård S., Fure H., Olstad O. K., Holden M., Lappegård K. T., Brekke O. L., Espevik T., Hovig E., Mollnes T. E. (2015) CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray. PLoS One 10, e0117261.
- Skjeflo E. W., Christiansen D., Espevik T., Nielsen E. W., Mollnes T. E. (2014) Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model. J. Immunol. 192, 2857–2864.
- Monoclonal Anti-TNF: A Randomized Controlled Sepsis Study Investigators (2004) Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit. Care Med. 32, 2173–2182.
- Opal S. M., Fisher C. J. Jr.,Dhainaut J. F., Vincent J. L., Brase R., Lowry S. F., Sadoff J. C., Slotman G. J., Levy H., Balk R. A., Shelly M. P., Pribble J. P., LaBrecque J. F., Lookabaugh J., Donovan H., Dubin H., Baughman R., Norman J., DeMaria E., Matzel K., Abraham E., Seneff M. (1997) Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit. Care Med. 25, 1115–1124.
- (2011) In brief: Xigris withdrawn. Med. Lett. Drugs Ther. 53, 104.
- Marshall J. C. (2003) Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat. Rev. Drug Discov. 2, 391–405.
- Meurens F., Summerfield A., Nauwynck H., Saif L., Gerdts V. (2012) The pig: a model for human infectious diseases. Trends Microbiol. 20, 50–57.
- Castellheim A., Thorgersen E. B., Hellerud B. C., Pharo A., Johansen H. T., Brosstad F., Gaustad P., Brun H., Fosse E., Tønnessen T. I., Nielsen E. W., Mollnes T. E. (2008) New biomarkers in an acute model of live Escherichia coli-induced sepsis in pigs. Scand. J. Immunol. 68, 75–84.
- Nielsen E. W., Hellerud B. C., Thorgersen E. B., Castellheim A., Pharo A., Lindstad J., Tønnessen T. I., Brandtzaeg P., Mollnes T. E. (2009) A new dynamic porcine model of meningococcal shock. Shock 32, 302–309.
- Barratt-Due A., Thorgersen E. B., Egge K., Pischke S., Sokolov A., Hellerud B. C., Lindstad J. K., Pharo A., Bongoni A. K., Rieben R., Nunn M., Scott H., Mollnes T. E. (2013) Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis. J. Immunol. 191, 819–827.
- Egge K. H., Thorgersen E. B., Pischke S. E., Lindstad J. K., Pharo A., Bongoni A. K., Rieben R., Nunn M. A., Barratt-Due A., Mollnes T. E. (2015) Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14. Immunobiology 220, 999–1005.
- Markiewski M. M., Nilsson B., Ekdahl K. N., Mollnes T. E., Lambris J. D. (2007) Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184–192.
- Ritis K., Doumas M., Mastellos D., Micheli A., Giaglis S., Magotti P., Rafail S., Kartalis G., Sideras P., Lambris J. D. (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802.
- Landsem A., Fure H., Christiansen D., Nielsen E. W., Østerud B., Mollnes T. E., Brekke O. L. (2015) The key roles of complement and tissue factor in Escherichia coli-induced coagulation in human whole blood. Clin. Exp. Immunol. 182, 81–89.
- Huber-Lang M., Barratt-Due A., Pischke S. E., Sandanger Ø., Nilsson P. H., Nunn M. A., Denk S., Gaus W., Espevik T., Mollnes T. E. (2014) Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. J. Immunol. 192, 5324–5331.
- Skjeflo E. W., Sagatun C., Dybwik K., Aam S., Urving S. H., Nunn M. A., Fure H., Lau C., Brekke O. L., Huber-Lang M., Espevik T., Barratt-Due A., Nielsen E. W., Mollnes T. E. (2015) Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. Crit. Care 19, 415.
- Egge K. H., Thorgersen E. B., Lindstad J. K., Pharo A., Lambris J. D., Barratt-Due A., Mollnes T. E. (2014) Post challenge inhibition of C3 and CD14 attenuates Escherichia coli-induced inflammation in human whole blood. Innate Immun. 20, 68–77.
- Lindenskov P. H., Castellheim A., Saugstad O. D., Mollnes T. E. (2015) Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies. Neonatology 107, 225–230.
- Castellheim A., Lindenskov P. H., Pharo A., Aamodt G., Saugstad O. D., Mollnes T. E. (2005) Meconium aspiration syndrome induces complement-associated systemic inflammatory response in newborn piglets. Scand. J. Immunol. 61, 217–225.
- Salvesen B., Fung M., Saugstad O. D., Mollnes T. E. (2008) Role of complement and CD14 in meconium-induced cytokine formation. Pediatrics 121, e496–e505.
- Vilahur G., Badimon L. (2014) Ischemia/reperfusion activates myocardial innate immune response: the key role of the Toll-like receptor. Front. Physiol. 5, 496.
- Banz Y., Rieben R. (2012) Role of complement and perspectives for intervention in ischemia-reperfusion damage. Ann. Med. 44, 205–217.
- Hillmen P., Young N. S., Schubert J., Brodsky R. A., Socié G., Muus P., Röth A., Szer J., Elebute M. O., Nakamura R., Browne P., Risitano A. M., Hill A., Schrezenmeier H., Fu C. L., Maciejewski J., Rollins S. A., Mojcik C. F., Rother R. P., Luzzatto L. (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243.
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