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.
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References
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, 1404–1413
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.
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, 310–318
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, 217–225
Choe, J., Kelker, M.S., and Wilson, I.A. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309, 581–585
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, 170–179
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, 1549–1556
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, 6107–6114
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, 1665–1671
Gay, N.J. and Gangloff, M. (2007) Structure and function of toll receptors and their ligands. Annu Rev Biochem 76, 141–165
Hawlisch, H. and Kohl, J. (2006) Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol Immunol 43, 13–21
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, 683–692
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, 3335–3346
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, 1279–1287
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, 906–917
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, 5
Kohl, J. (2006) The role of complement in danger sensing and transmission. Immunol Res 34, 157–176
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, 47834–47843
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, 190–198
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, 2084–2092
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, 810–817
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, 657–662
Mollnes, T.E. and Kirschfink, M. (2006) Strategies of therapeutic complement inhibition. Mol Immunol 43, 107–121
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, 1869–1877
Mollnes, T.E., Song, W.C., and Lambris, J.D. (2002b) Complement in inflammatory tissue damage and disease. Trends Immunol 23, 61–64
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, 3838–3849
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, 1632–1634
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 370–372
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, 503–507
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–e505
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, 4210–4219
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–I274
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, 3344–3349
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, 282–285
Uematsu, S. and Akira, S. (2007) Toll-like receptors and type I interferons. J Biol Chem 282, 15319–15323
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, 2655–2660
Walport, M.J. (2001a) Advances in immunology: complement (First of two parts). N Engl J Med 344, 1058–1066
Walport, M.J. (2001b) Advances in immunology: complement (Second of two parts). N Engl J Med 344, 1140–1144
Ward, P.A. (2004) The dark side of C5A in sepsis. Nat Rev Immunol 4, 133–142
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, 518–524
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, 221–230
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, 430–433
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, 1575–1582
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, 228–236
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Mollnes, T., Christiansen, D., Brekke, OL., Espevik, T. (2008). Hypothesis: Combined Inhibition of Complement and CD14 as Treatment Regimen to Attenuate the Inflammatory Response. In: Lambris, J. (eds) Current Topics in Complement II. Advances in Experimental Medicine and Biology, vol 632. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78952-1_18
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DOI: https://doi.org/10.1007/978-0-387-78952-1_18
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