New aspects of the C5a receptor

DOI: 10.4236/abb.2014.51009   PDF   HTML   XML   4,251 Downloads   5,724 Views  


The process of apoptotic cell death for maintenance of cell homeostasis is now believed to be flexible. To examine the mechanism for this flexibility, the process of programmed cell death is sometimes divided into three phases: initiation, effector and execution. We have demonstrated that apoptotic cells commonly express a de novo synthesized C5a receptor (C5aR), which belongs to the G protein-coupled receptor (GPCR) family. A natural agnostic ligand of the C5aR, C5a, is produced from plasma C5 by C5 convertase in the early phase of acute inflammation. Although it is not realistic, we found that C5a can adjust apoptotic cell lifespan long. We recently have read interesting reports that apoptotic cells can release natural agnostic ligands at the initiation phase and corresponding GPCRs are already expressed on cell surfaces of apoptotic cells. Conversely, we found that apoptotic cells commonly release an alternative antagonistic/agnostic ligand of the de novo synthesized C5aR, ribosomal protein S19 (RP S19) polymer. The RP S19 polymer can adjust apoptotic cell lifespan short. Importantly, the C5a-dependent regulation is limited by the C5aR sensitization, but the RP S19 polymer-dependent regulation is unlimited by the C5aR desensitization. Therefore, we suggested that apoptotic cells commonly release agnostic ligands in the initiation phase that should lengthen intermittently a period of the initiation phase. Next, apoptotic cells commonly release antagonistic/agnostic ligands in the effector phase that should continue shortening a period of the effector phase. In addition, we know that an inherited erythroblastopenia is associated with mutations in the RP S19 gene. However, the roles of RP S19 in the formation of erythroblast-macrophage islands are not clearly understood. We recently have found that a different arm that the RP S19 polymer has connects the de novo synthesized C5aR on erythroblasts and the generally expressed C5aR on macrophages. Therefore, we suggested that apoptotic cells commonly release antagonistic/agnostic ligands in the execution phase that should continue connecting apoptotic cells and macrophages in the execution phase for shortening a period of the execution phase. In this review, we introduce new aspects of the C5aR in apoptotic cells and discuss the effects of the long lifespan of apoptotic cell-like neutrophils on the development of periodontitis.

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Nishiura, H. and Ohura, K. (2014) New aspects of the C5a receptor. Advances in Bioscience and Biotechnology, 5, 54-63. doi: 10.4236/abb.2014.51009.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Nagata, S. (2010) Apoptosis and autoimmune diseases. Annals of the New York Academy of Sciences, 1209, 10-16.
[2] Gonzalez, V.M., Fuertes, M.A., Alonso, C. and Perez J.M. (2001) Is cisplatin-induced cell death always produced by apoptosis? Molecular pharmacology, 59, 657-663.
[3] Ravichandran, K.S. (2011) Beginnings of a good apoptotic meal: The find-me and eat-me signaling pathways. Immunity, 35, 445-455.
[4] White, G.E. and Greaves D.R. (2012) Fractalkine: A survivor’s guide: Chemokines as antiapoptotic mediators. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 589-594.
[5] Hait, N.C., Oskeritzian, C.A., Paugh, S.W., Milstien, S. and Spiegel, S. (2006) Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochimica et Biophysica Acta, 1758, 2016-2026.
[6] Jia, N., Semba, U., Nishiura, H, Kuniyasu, A., Nsiama, T.K., Nishino, N. and Yamamoto, T. (2010) Pivotal Advance: Interconversion between pure chemotactic ligands and chemoattractant/secretagogue ligands of neutrophil C5a receptor by a single amino acid substitution. Journal of Leukocyte Biology, 87, 965-975.
[7] Freire, M.O. and Van Dyke, T.E. (2013) Natural resolution of inflammation. Periodontology 2000, 63, 149-164.
[8] Legrand, D. (2012) Lactoferrin, a key molecule in immune and inflammatory processes. Biochemistry and Cell Biology, 90, 252-268.
[9] Bournazou, I., Pound, J.D., Duffin, R., Bournazos, S., Melville, L.A., Brown, S.B., Rossi, A.G. and Gregory C. D. (2009) Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. Journal of Clinical Investigation, 119, 20-32.
[10] Wong, S.H., Francis, N., Chahal, H., Raza, K., Salmon, M., Scheel-Toellner, D. and Lord J.M. (2009) Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluid. Rheumatology (Oxford), 48, 39-44.
[11] Youn, B.S., Yu, K.Y., Oh, J., Lee, J., Lee, T.H. and Broxmeyer, H.E. (2002) Role of the CC chemokine receptor 9/TECK interaction in apoptosis. Apoptosis, 7, 271-276.
[12] Nishiura, H., Nonaka, H., Revollo, I.S., Semba, U., Li, Y., Ota, Y., Irie, A., Harada, K., Kehrl, J.H. and Yamamoto, T. (2009) Pro- and anti-apoptotic dual functions of the C5a receptor: Involvement of regulator of G protein signaling 3 and extracellular signal-regulated kinase. Laboratory Investigation, 89, 676-694.
[13] Milligan, G. (2003) Constitutive activity and inverse agonists of G protein-coupled receptors: A current perspective. Molecular Pharmacology, 64, 1271-1276.
[14] Miyanishi, M., Segawa, K. and Nagata, S. (2012) Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. International Immunology, 24, 551-559.
[15] Kristof, E., Zahuczky, G., Katona, K., Doro, Z., Nagy, E. and Fesus, L. (2013) Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis, 18, 1235-1251.
[16] Nishiura, H., Tanaka, J., Takeya, M., Tsukano, M., Kambara, T. and Imamura T. (1996) IL-8/NAP-1 is the major T-cell chemoattractant in synovial tissues of rheumatoid arthritis. Clinical Immunology and Immunopathology, 80, 179-184.
[17] Nishiura, H., Shibuya, Y., Matsubara, S., Tanase, S., Kambara, T. and Yamamoto, T. (1996) Monocyte chemotactic factor in rheumatoid arthritis synovial tissue. Probably a cross-linked derivative of S19 ribosomal protein. The Journal of Biological Chemistry, 271, 878-882.
[18] Nishiura, H., Zhao, R. and Yamamoto, T. (2011) The role of the ribosomal protein S19 C-terminus in altering the chemotaxis of leukocytes by causing functional differences in the C5a receptor response. The Journal of Biochemistry.
[19] Hunt, J.R., Martin, C.B. and Martin, B.K. (2005) Transcriptional regulation of the murine C5a receptor gene: NF-Y is required for basal and LPS induced expression in macrophages and endothelial cells. Molecular Immunology, 42, 1405-1415.
[20] Snyderman, R., Phillips, J.K. and Mergenhagen, S.E. (1971) Biological activity of complement in vivo. Role of C5 in the accumulation of polymorphonuclear leukocytes in inflammatory exudates. The Journal of Experimental medicine, 134, 1131-1143.
[21] Hopken, U.E., Lu, B., Gerard, N.P. and Gerard, C. (1997) Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor. The Journal of Experimental Medicine, 186, 749-756.
[22] Monk, P.N., Scola, A.M., Madala, P. and Fairlie, D.P. (2007) Function, structure and therapeutic potential of complement C5a receptors. British Journal of Pharmacology, 152, 429-448.
[23] Cook, W.J., Galakatos, N., Boyar, W.C., Walter, R.L. and Ealick, S.E. (2010) Structure of human desArg-C5a. Biological Crystallography, 66, 190-197.
[24] Hagemann, I.S., Miller, D.L., Klco, J.M., Nikiforovich, G.V. and Baranski, T.J. (2008) Structure of the complement factor 5a receptor-ligand complex studied by disulfide trapping and molecular modeling. The Journal of Biological Chemistry, 283, 7763-7775.
[25] Roed, S.N., Orgaard, A., Jorgensen, R. and De Meyts, P. (2012) Receptor oligomerization in family B1 of G-protein-coupled receptors: focus on BRET investigations and the link between GPCR oligomerization and binding cooperativity. Frontiers in Endocrinology (Lausanne), 3, 62.
[26] Nishiura, H., Chen, J., Ota, Y., Semba, U., Higuchi, H., Nakashima, T. and Yamamoto, T. (2010) Base of molecular mimicry between human ribosomal protein S19 dimer and human C5a anaphylatoxin. International Immunopharmacology, 10, 1541-1547.
[27] Cathcart, M.K. (2009) Signal-activated phospholipase regulation of leukocyte chemotaxis. The Journal of Lipid Research, 50, S231-S236.
[28] Mollapour, E., Linch, D.C. and Roberts, P.J. (2001) Activation and priming of neutrophil nicotinamide adenine dinucleotide phosphate oxidase and phospholipase A(2) are dissociated by inhibitors of the kinases p42(ERK2) and p38(SAPK) and by methyl arachidonyl fluorophosphonate, the dual inhibitor of cytosolic and calcium-independent phospholipase A(2). Blood, 97, 2469-2477.
[29] Nishiura, H., Tanase, S., Sibuya, Y., Nishimura, T. and Yamamoto, T. (1999) Determination of the cross-linked residues in homo-dimerization of S19 ribosomal protein concomitant with exhibition of monocyte chemotactic activity. Laboratory Investigation, 79, 915-923.
[30] Nishiura, H., Shibuya, Y. and Yamamoto, T. (1998) S19 ribosomal protein cross-linked dimer causes monocytepredominant infiltration by means of molecular mimicry to complement C5a. Laboratory Investigation, 78, 1615-1623.
[31] Arumugam, T.V., Shiels, I.A., Woodruff, T.M., Reid, R.C., Fairlie, D.P. and Taylor, S.M. (2002) Protective effect of a new C5a receptor antagonist against ischemia-reperfusion injury in the rat small intestine. Journal of Surgical Research, 103, 260-267.
[32] Gregory, L.A., Aguissa-Toure, A.H., Pinaud, N., Legrand, P., Gleizes, P.E. and Fribourg, S. (2007) Molecular basis of Diamond-Blackfan anemia: Structure and function analysis of RPS19. Nucleic Acids Research, 35, 5913-5921.
[33] Horino, K., Nishiura, H., Ohsako, T., Shibuya, Y., Hiraoka, T., Kitamura, N. and Yamamoto, T. (1998) A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Laboratory Investigation, 78, 603-617.
[34] Nishimura, T., Horino, K., Nishiura, H., Shibuya, Y., Hiraoka, T., Tanase, S. and Yamamoto, T. (2001) Apoptotic cells of an epithelial cell line, AsPC-1, release monocyte chemotactic S19 ribosomal protein dimer. The Journal of Biochemistry, 129, 445-454.
[35] Nishiura, H., Tanase, S., Shibuya, Y., Futa, N., Sakamoto, T., Higginbottom, A., Monk, P., Zwirner, J. and Yamamoto, T. (2005) S19 ribosomal protein dimer augments metal-induced apoptosis in a mouse fibroblastic cell line by ligation of the C5a receptor. Journal of Cellular Biochemistry, 94, 540-553.
[36] Shrestha, A., Shiokawa, M., Nishimura, T., Nishiura, H., Tanaka, Y., Nishino, N., Shibuya, Y. and Yamamoto, T. (2003) Switch moiety in agonist/antagonist dual effect of S19 ribosomal protein dimer on leukocyte chemotactic C5a receptor. The American Journal of Pathology, 162, 1381-1388.
[37] Regal, J.F. and Fraser, D.G. (1990) Recombinant human C5a-induced bronchoconstriction in the guinea-pig: A histamine independent mechanism. Pulmonary Pharmacology, 3, 79-87.
[38] Oda, Y., Tokita, K., Ota, Y., Li, Y., Taniguchi, K., Nishino, N., Takagi, K., Yamamoto, T. and Nishiura, H. (2008) Agonistic and antagonistic effects of C5a-chimera bearing S19 ribosomal protein tail portion on the C5a receptor of monocytes and neutrophils, respectively. Journal of Biochemistry, 144, 371-381.
[39] Nishiura, H., Tokita, K., Li, Y., Harada, K., Woodruff, T.M., Taylor, S.M., Nsiama, T.K., Nishino, N. and Yamamoto, T. (2010) The role of the ribosomal protein S19 C-terminus in Gi protein-dependent alternative activation of p38 MAP kinase via the C5a receptor in HMC-1 cells. Apoptosis, 15, 966-981.
[40] Nishiura, H., Tanase, S., Tsujita, K., Sugiyama, S., Ogawa, H., Nakagaki, T., Semba, U. and Yamamoto, T. (2011) Maintenance of ribosomal protein S19 in plasma by complex formation with prothrombin. European Journal of Haematology, 86, 436-441.
[41] Song, H., Wohltmann, M., Tan, M., Bao, S., Ladenson, J.H. and Turk, J. (2011) Group VIA PLA2 (iPLA2β) is activated upstream of p38 MAP kinase in pancreatic islet β cell signaling. The Journal of Biological Chemistry, 287, 5528-5541.
[42] Knizhnik, A.V., Kovaleva, O.V., Komelkov, A.V., Trukhanova, L.S., Rybko, V.A., Zborovskaya, I.B. and Tchevkina, E.M. (2012) Arf6 promotes cell proliferation via the PLD-mTORC1 and p38MAPK pathways. Journal of Cellular Biochemistry, 113, 360-371.
[43] Harteneck, C. (2005) Function and pharmacology of TRPM cation channels. Naunyn-Schmiedeberg’s Archives of Pharmacology, 371, 307-314.
[44] Jenkins, C.M., Wolf, M.J., Mancuso, D.J. and Gross, R.W. (2001) Identification of the calmodulin-binding domain of recombinant calcium-independent phospholipase A2β. Implications for structure and function. The Journal of Biological Chemistry, 276, 7129-7135.
[45] Mason, M.J., Schaffner, C., Floto, R.A. and Teo, Q.A. (2012) Constitutive expression of a Mg2+-inhibited K+ current and a TRPM7-like current in human erythroleukemia cells. American Journal of Physiology-Cell Physiology, 302, C853-C867.
[46] Perianayagam, M.C., Balakrishnan, V.S., Pereira, B.J. and Jaber, B.L. (2004) C5a delays apoptosis of human neutrophils via an extracellular signal-regulated kinase and Bad-mediated signalling pathway. European Journal of Clinical Investigation, 34, 50-56.
[47] Matsson, H., Klar, J., Draptchinskaia, N., Gustavsson, P., Carlsson, B., Bowers, D., de Bont, E. and Dahl, N. (1999) Truncating ribosomal protein S19 mutations and variable clinical expression in diamond-blackfan anemia. Human Genetics, 105, 496-500.
[48] Nishiura, H., Zhao, R. and Yamamoto, T. (2012) Dual functions of the C5a receptor as a connector for the K562 erythroblast-like cell-THP-1 macrophage-like cell island and as a sensor for the differentiation of the K562 erythroblast-like cell during haemin-induced erythropoiesis. Clinical and Developmental Immunology, 2012, Article ID: 187080.
[49] Rabiet, M.J., Macari, L., Dahlgren, C. and Boulay, F. (2011) N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. The Journal of Biological Chemistry, 286, 26718-26731.
[50] Migeotte, I., Riboldi, E., Franssen, J.D., Gregoire, F., Loison, C., Wittamer, V., Detheux, M., Robberecht, P., Costagliola, S., Vassart, G., Sozzani, S., Parmentier, M. and Communi, D. (2005) Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. The Journal of Experimental Medicine, 201, 83-93.
[51] Parente, L. and Solito, E. (2004) Annexin 1: More than an anti-phospholipase protein. Inflammation Research, 53, 125-132.
[52] Yokomizo, T., Kato, K., Terawaki, K., Izumi, T. and Shimizu, T. (2000) A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. The Journal of Experimental Medicine, 192, 421-432.
[53] Agnihotri, R. and Gaur, S. (2013) Rheumatoid arthritis in the elderly and its relationship with periodontitis: A review. Geriatrics & Gerontology International.
[54] Wakabayashi, H., Kondo, I., Kobayashi, T., Yamauchi, K., Toida, T., Iwatsuki, K. and Yoshie, H. (2010) Periodontitis, periodontopathic bacteria and lactoferrin. Biometal: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine, 23, 419-424.
[55] Ogrendik, M. (2012) Does periodontopathic bacterial infection contribute to the etiopathogenesis of the autoimmune disease rheumatoid arthritis? Discovery Medicine, 13, 349-355
[56] Scott, D.A. and Krauss, J. (2012) Neutrophils in periodontal inflammation. Frontiers of Oral Biology, 15, 56-83.
[57] Wingrove, J.A., DiScipio, R.G., Chen, Z., Potempa, J., Travis, J. and Hugli, T.E. (1992) Activation of complement components C3 and C5 by a cysteine proteinase (gingipain-1) from Porphyromonas (Bacteroides) gingivalis. The Journal of Biological Chemistry, 267, 18902-18907
[58] Jagels, M.A., Ember, J.A., Travis, J., Potempa, J., Pike, R. and Hugli, T.E. (1996) Cleavage of the human C5A receptor by proteinases derived from Porphyromonas gingivalis: Cleavage of leukocyte C5a receptor. Advances in Experimental Medicine and Biology, 389, 155-164.
[59] Jusko, M., Potempa, J., Karim, A.Y., Ksiazek, M., Riesbeck, K., Garred, P., Eick, S. and Blom, A.M. (2012) A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system. Journal of Immunology, 188, 2338-2349.
[60] Johansson, A. (2011) Aggregatibacter actinomycetemcomitans leukotoxin: A powerful tool with capacity to cause imbalance in the host inflammatory response. Toxins, 3, 242-259.
[61] Belibasakis, G.N., Mattsson, A., Wang, Y., Chen, C. and Johansson, A. (2004) Cell cycle arrest of human gingival fibroblasts and periodontal ligament cells by Actinobacillus actinomycetemcomitans: Involvement of the cytolethal distending toxin. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica, 112, 674-685.
[62] Ohura, K., Shinohara, M., Ogata, K., Nishiyama, A. and Mori, M. (1990) Leucocyte function in rats with naturally occurring gingivitis. Archives of Oral Biology, 35, S185-S187.
[63] Konakajima, Y., Tani, A., Ohura, K., Shinohara, M., Ogata, K., Mori, M. and Sagawa, H. (1990) Humoral immune responses in experimental gingivitis in rats. Archives of Oral Biology, 35, S181-S183.

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