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Hypothesis: Combined Inhibition of Complement and CD14 as Treatment Regimen to Attenuate the Inflammatory Response

  • Tom Eirik Mollnes
  • Dorte Christiansen
  • Ole-Lars Brekke
  • Terje Espevik
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 632)

Abstract

Pattern recognition is an essential event in innate immunity. Complement and Toll-like receptors (TLR), including the CD14 molecule, are two important upstream components of the innate immune system, recognizing exogenous structures as well as endogenous ligands. They act partly independent in the inflammatory network, but also have several cross-talk mechanisms which are under current investigation. Complement is an essential part of innate immunity protecting the host against infection. However, it is a double-edged sword since inappropriate activation may damage the host. Uncontrolled systemic activation of complement, as seen in severe sepsis, may contribute to the breakdown of homeostatic mechanisms leading to the irreversible state of septic shock. Complement inhibition is promising for protection of lethal experimental sepsis, but clinical studies are missing. Lipopolysaccharide (LPS) has been implicated in the pathogenesis of gram-negative sepsis by inducing synthesis of pro-inflammatory cytokines through binding to CD14 and the TLR4/MD-2 complex. Neutralization of LPS or blocking of CD14 has been effective in preventing LPS-induced lethal shock in animal studies, but results from clinical studies have been disappointing, as for most other therapeutic strategies. Based on some recently published data and further pilot data obtained in our laboratory, we hypothesize that inhibition of complement combined with neutralization of CD14 may attenuate the uncontrolled inflammatory reaction which leads to breakdown of homeostasis during sepsis. We further postulate this regimen as an approach for efficient inhibition of the initial innate recognition, exogenous as well as endogenous, to prevent downstream activation of the inflammatory reaction in general.

Keywords

Systemic Inflammatory Response Syndrome Combine Inhibition Inflammatory System Meconium Aspiration Syndrome Blood Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Brekke, O.L., Christiansen, D., Fure, H., Fung, M., and 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, 1404–1413PubMedCrossRefGoogle Scholar
  2. Brekke, O.L., Christiansen, D., Fure, H., Pharo, A., Fung, M., Riesenfeld, J., and 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.PubMedCrossRefGoogle Scholar
  3. Castellheim, A., Lindenskov, P.H., Pharo, A., Fung, M., Saugstad, O.D., and Mollnes, T.E. (2004) Meconium is a potent activator of complement in human serum and in piglets. Pediatr Res 55, 310–318PubMedCrossRefGoogle Scholar
  4. Castellheim, A., Lindenskov, P.H., Pharo, A., Aamodt, G., Saugstad, O.D., and Mollnes, T.E. (2005) Meconium aspiration syndrome induces complement-associated systemic inflammatory response in newborn piglets. Scand J Immunol 61, 217–225PubMedCrossRefGoogle Scholar
  5. Choe, J., Kelker, M.S., and Wilson, I.A. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585PubMedCrossRefGoogle Scholar
  6. Chong, A.J., Shimamoto, A., Hampton, C.R., Takayama, H., Spring, D.J., Rothnie, C.L., Yada, M., Pohlman, T.H., and Verrier, E.D. (2004) Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg 128, 170–179PubMedCrossRefGoogle Scholar
  7. Collard, C.D., Vakeva, A., Morrissey, M.A., Agah, A., Rollins, S.A., Reenstra, W.R., Buras, J.A., Meri, S., and Stahl, G.L. (2000) Complement activation after oxidative stress – role of the lectin complement pathway. Am J Pathol 156, 1549–1556PubMedCrossRefGoogle Scholar
  8. Daubeuf, B., Mathison, J., Spiller, S., Hugues, S., Herren, S., Ferlin, W., Kosco-Vilbois, M., Wagner, H., Kirschning, C.J., Ulevitch, R., and Elson, G. (2007) TLR4/MD-2 Monoclonal antibody therapy affords protection in experimental models of septic shock. J Immunol 179, 6107–6114PubMedGoogle Scholar
  9. Frey, E.A., Miller, D.S., Jahr, T.G., Sundan, A., Bazil, V., Espevik, T., Finlay, B.B., and Wright, S.D. (1992) Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med 176, 1665–1671PubMedCrossRefGoogle Scholar
  10. Gay, N.J. and Gangloff, M. (2007) Structure and function of toll receptors and their ligands. Annu Rev Biochem 76, 141–165PubMedCrossRefGoogle Scholar
  11. Hawlisch, H. and Kohl, J. (2006) Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol Immunol 43, 13–21PubMedCrossRefGoogle Scholar
  12. Husebye, H., Halaas, O., Stenmark, H., Tunheim, G., Sandanger, O., Bogen, B., Brech, A., Latz, E., and Espevik, T. (2006) Endocytic pathways regulate toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J 25, 683–692PubMedCrossRefGoogle Scholar
  13. Johnsen, I.B., Nguyen, T.T., Ringdal, M., Tryggestad, A.M., Bakke, O., Lien, E., Espevik, T., and Anthonsen, M.W. (2006) Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling. EMBO J 25, 3335–3346PubMedCrossRefGoogle Scholar
  14. Kaczorowski, D.J., Nakao, A., Mollen, K.P., Vallabhaneni, R., Sugimoto, R., Kohmoto, J., Tobita, K., Zuckerbraun, B.S., Mccurry, K.R., Murase, N., and Billiar, T.R. (2007) Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. Transplantation 84, 1279–1287PubMedCrossRefGoogle Scholar
  15. Kim, H.M., Park, B.S., Kim, J.I., Kim, S.E., Lee, J., Oh, S.C., Enkhbayar, P., Matsushima, N., Lee, H., Yoo, O.J., and Lee, J.O. (2007a) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 130, 906–917CrossRefGoogle Scholar
  16. Kim, S.C., Ghanem, A., Stapel, H., Tiemann, K., Knuefermann, P., Hoeft, A., Meyer, R., Grohe, C., Knowlton, A.A., and Baumgarten, G. (2007b) Toll-like receptor 4 deficiency: smaller infarcts, but no gain in function. BMC Physiol 7, 5CrossRefGoogle Scholar
  17. Kohl, J. (2006) The role of complement in danger sensing and transmission. Immunol Res 34, 157–176PubMedCrossRefGoogle Scholar
  18. Latz, E., Visintin, A., Lien, E., Fitzgerald, K.A., Monks, B.G., Kurt-Jones, E.A., Golenbock, D.T., and 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, 47834–47843PubMedCrossRefGoogle Scholar
  19. Latz, E., Schoenemeyer, A., Visintin, A., Fitzgerald, K.A., Monks, B.G., Knetter, C.F., Lien, E., Nilsen, N.J., Espevik, T., and Golenbock, D.T. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5, 190–198PubMedCrossRefGoogle Scholar
  20. Lien, E., Aukrust, P., Sundan, A., Muller, F., Froland, S.S., and Espevik, T. (1998) Elevated levels of serum-soluble CD14 in human immunodeficiency virus type 1 (HIV-1) infection: correlation to disease progression and clinical events. Blood 92, 2084–2092PubMedGoogle Scholar
  21. Lindenskov, P.H., Castellheim, A., Aamodt, G., Saugstad, O.D., and Mollnes, T.E. (2004) Complement activation reflects severity of meconium aspiration syndrome in newborn pigs. Pediatr Res 56, 810–817PubMedCrossRefGoogle Scholar
  22. Marchant, A., Tielemans, C., Husson, C., Gastaldello, K., Schurmans, T., De, G.D., Duchow, J., Vanherweghem, L., and Goldman, M. (1996) Cuprophane haemodialysis induces upregulation of LPS receptor (CD14) on monocytes: role of complement activation. Nephrol Dial Transplant 11, 657–662PubMedGoogle Scholar
  23. Mollnes, T.E. and Kirschfink, M. (2006) Strategies of therapeutic complement inhibition. Mol Immunol 43, 107–121PubMedCrossRefGoogle Scholar
  24. Mollnes, T.E., Brekke, O.L., Fung, M., Fure, H., Christiansen, D., Bergseth, G., Videm, V., Lappegard, K.T., Kohl, J., and Lambris, J.D. (2002a) 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, 1869–1877Google Scholar
  25. Mollnes, T.E., Song, W.C., and Lambris, J.D. (2002b) Complement in inflammatory tissue damage and disease. Trends Immunol 23, 61–64CrossRefGoogle Scholar
  26. Mollnes, T.E., Jokiranta, T.S., Truedsson, L., Nilsson, B., Rodriguez de, C.S., and Kirschfink, M. (2007) Complement analysis in the 21st century. Mol Immunol 44, 3838–3849PubMedCrossRefGoogle Scholar
  27. Ohto, U., Fukase, K., Miyake, K., and Satow, Y. (2007) Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science 316, 1632–1634PubMedCrossRefGoogle Scholar
  28. Riedemann, N.C., Guo, R.F., Hollmann, T.J., Gao, H., Neff, T.A., Reuben, J.S., Speyer, C.L., Sarma, J.V., Wetsel, R.A., Zetoune, F.S., and Ward, P.A. (2003a) Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J 370–372Google Scholar
  29. Riedemann, N.C., Neff, T.A., Guo, R.F., Bernacki, K.D., Laudes, I.J., Sarma, J.V., Lambris, J.D., and Ward, P.A. (2003b) Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol 170, 503–507Google Scholar
  30. Salvesen, B., Fung, M., Saugstad, O.D., and Mollnes, T.E. (2008) The role of complement and CD14 in meconium-induced cytokine formation. Pediatrics 121, e496–e505PubMedCrossRefGoogle Scholar
  31. Sendide, K., Reiner, N.E., Lee, J.S., Bourgoin, S., Talal, A., and 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, 4210–4219PubMedGoogle Scholar
  32. Shimamoto, A., Chong, A.J., Yada, M., Shomura, S., Takayama, H., Fleisig, A.J., Agnew, M.L., Hampton, C.R., Rothnie, C.L., Spring, D.J., Pohlman, T.H., Shimpo, H., and Verrier, E.D. (2006) Inhibition of toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation 114, I270–I274PubMedCrossRefGoogle Scholar
  33. Sprong, T., Moller, A.S., Bjerre, A., Wedege, E., Kierulf, P., van der Meer, J.W., Brandtzaeg, P., van Deuren, M., and Mollnes, T.E. (2004) Complement activation and complement-dependent inflammation by Neisseria meningitidis are independent of lipopolysaccharide. Infect Immun 72, 3344–3349PubMedCrossRefGoogle Scholar
  34. Tang, A.H., Brunn, G.J., Cascalho, M., and Platt, J.L. (2007) Pivotal advance: endogenous pathway to SIRS, sepsis, and related conditions. J Leukoc Biol 82, 282–285PubMedCrossRefGoogle Scholar
  35. Uematsu, S. and Akira, S. (2007) Toll-like receptors and type I interferons. J Biol Chem 282, 15319–15323PubMedCrossRefGoogle Scholar
  36. van Bruggen, R., Zweers, D., van, D.A., van Dissel, J.T., Roos, D., Verhoeven, A.J., and Kuijpers, T.W. (2007) Complement receptor 3 and Toll-like receptor 4 act sequentially in uptake and intracellular killing of unopsonized Salmonella enterica serovar typhimurium. by human neutrophils Infect Immun 75, 2655–2660PubMedCrossRefGoogle Scholar
  37. Walport, M.J. (2001a) Advances in immunology: complement (First of two parts). N Engl J Med 344, 1058–1066CrossRefGoogle Scholar
  38. Walport, M.J. (2001b) Advances in immunology: complement (Second of two parts). N Engl J Med 344, 1140–1144CrossRefGoogle Scholar
  39. Ward, P.A. (2004) The dark side of C5A in sepsis. Nat Rev Immunol 4, 133–142PubMedCrossRefGoogle Scholar
  40. Weingarten, R., Sklar, L.A., Mathison, J.C., Omidi, S., Ainsworth, T., Simon, S., Ulevitch, R.J., and Tobias, P.S. (1993) Interactions of lipopolysaccharide with neutrophils in blood via CD14. J Leukoc Biol 53, 518–524PubMedGoogle Scholar
  41. Yamada, M., Oritani, K., Kaisho, T., Ishikawa, J., Yoshida, H., Takahashi, I., Kawamoto, S., Ishida, N., Ujiie, H., Masaie, H., Botto, M., Tomiyama, Y., and Matsuzawa, Y. (2004) Complement C1q regulates LPS-induced cytokine production in bone marrow-derived dendritic cells. Eur J Immunol 34, 221–230PubMedCrossRefGoogle Scholar
  42. Zarewych, D.M., Kindzelskii, A.L., Todd, R.F., III, and Petty, H.R. (1996) LPS induces CD14 association with complement receptor type 3, which is reversed by neutrophil adhesion. J Immunol 156, 430–433PubMedGoogle Scholar
  43. Zhang, M. and Carroll, M.C. (2007) Natural IgM-mediated innate autoimmunity: a new target for early intervention of ischemia-reperfusion injury. Expert Opin Biol Ther 7, 1575–1582PubMedCrossRefGoogle Scholar
  44. Zhang, X., Kimura, Y., Fang, C., Zhou, L., Sfyroera, G., Lambris, J.D., Wetsel, R.A., Miwa, T., and Song, W.C. (2007) Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228–236PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Tom Eirik Mollnes
    • 1
  • Dorte Christiansen
    • 3
  • Ole-Lars Brekke
    • 2
  • Terje Espevik
    • 4
  1. 1.Institute of ImmunologyUniversity of Oslo, and Rikshospitalet University HospitalOsloNorway
  2. 2.Department of Laboratory Medicine, Nordland Hospital Bodø, and Institute of Medical BiologyUniversity of TromsøTromsøNorway
  3. 3.Department of Laboratory MedicineNordland HospitalBodøNorway
  4. 4.Department of Cancer Research and Molecular MedicineNorwegian University of Science and TechnologyTrondheimNorway

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