The Alternative C5a Receptor Function

  • Hiroshi NishiuraEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 735)


When acute inflammatory states are induced by treatment with chemical mediators in C5-deficient mice, neutrophil influxes are commonly decreased. Therefore, the neutrophil C5a receptor (C5aR) is believed to be a member of the pro-inflammatory receptors. However, C5aR deficiency endows mouse neutrophils with increased sensitivity to Pseudomonas aeruginosa. We have demonstrated that C5aR accepts not only C5a but also ribosomal protein S19 (RP S19) oligomers. RP S19 oligomers released from apoptotic cells promote apoptosis or induce dual agonistic and antagonistic effects on the chemotaxis of macrophages and neutrophils in an autocrine or paracrine manner, respectively. We assumed that the function of C5aR in apoptotic cells is almost the same as that in neutrophils infiltrating acute inflammatory lesions. Therefore, we believe that RP S19 oligomers can explain the opposite response of neutrophils in C5aR-deficient mice. In the present study, we found that anti-human RP S19 rabbit IgG cross-reacted with mouse RP S19 monomers and oligomers in plasma and serum, respectively, whereas anti-human C5a rabbit IgG only cross-reacted with mouse RP S19 oligomers in serum. To examine a role of RP S19 oligomers in vivo, we injected carrageenan (50 μg/100 μL) into the thoracic cavities of mice in the simultaneous presence of rabbit IgG and anti-human C5a rabbit IgG (100 μg/100 μL). Before 4 h and after 24 h, we did not observe any inflammatory cues in pleural exudates and lung substances from control mice. However, infiltrating neutrophils were detected in pleural exudates and lung tissues at 4 h after the addition of anti-human RP S19 rabbit IgG. Moreover, anti-human C5a rabbit IgG retards the initiation phase of carrageenan-induced mouse plurality. Many of the neutrophils infiltrating the thoracic cavities of the mice remained annexin V-negative. Neutrophil infiltration into pneumonic lesions became more severe, as alveolar septal destruction and haemorrhage concomitant with increased numbers of neutrophils in the pleural exudates were observed. These in vivo data demonstrate that the neutrophil C5aR acts as a dual pro-inflammatory and pro-apoptosis receptor during the initiation and the resolution phases of acute inflammation, respectively.


Acute Inflammation Neutrophil Influx Arthus Reaction Pleural Exudate Coagulation Factor Xiii 
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.



This work was supported by Grant-in-Aid for Scientific Research (C) (Nishiura; KAKENHI 22590362) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


  1. Bansal G, Druey KM, Xie Z (2007) R4 RGS proteins: regulation of G-protein signaling and beyond. Pharmacol Ther 116:473–495CrossRefGoogle Scholar
  2. Bournazou I, Pound JD, Duffin R, Bournazos S, Melville LA, Brown SB, Rossi AG, Gregory CD (2009) Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. J Clin Invest 119:20–32PubMedGoogle Scholar
  3. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, Armstrong AJ, Penuela S, Laird DW, Salvesen GS et al (2010) Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:863–867CrossRefGoogle Scholar
  4. Elorza A, Sarnago S, Mayor F Jr (2000) Agonist-dependent modulation of G protein-coupled receptor kinase 2 by mitogen-activated protein kinases. Mol Pharmacol 57:778–783CrossRefGoogle Scholar
  5. Filip AM, Klug J, Cayli S, Frohlich S, Henke T, Lacher P, Eickhoff R, Bulau P, Linder M, Carlsson-Skwirut C et al (2009) Ribosomal protein S19 interacts with macrophage migration inhibitory factor and attenuates its pro-inflammatory function. J Biol Chem 284:7977–7985CrossRefGoogle Scholar
  6. Garcia-Ramallo E, Marques T, Prats N, Beleta J, Kunkel SL, Godessart N (2002) Resident cell chemokine expression serves as the major mechanism for leukocyte recruitment during local inflammation. J Immunol 169:6467–6473CrossRefGoogle Scholar
  7. Gerard NP, Bao L, Xiao-Ping H, Eddy RL Jr, Shows TB, Gerard C (1993) Human chemotaxis receptor genes cluster at 19q13.3–13.4. Characterization of the human C5a receptor gene. Biochemistry 32:1243–1250CrossRefGoogle Scholar
  8. Hopken UE, Lu B, Gerard NP, Gerard C (1996) The C5a chemoattractant receptor mediates mucosal defence to infection. Nature 383:86–89CrossRefGoogle Scholar
  9. Hopken UE, Lu B, Gerard NP, Gerard C (1997) Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor. J Exp Med 186:749–756CrossRefGoogle Scholar
  10. Horino K, Nishiura H, Ohsako T, Shibuya Y, Hiraoka T, Kitamura N, Yamamoto T (1998) A monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest 78:603–617PubMedGoogle Scholar
  11. Jia N, Semba U, Nishiura H, Kuniyasu A, Nsiama TK, Nishino N, Yamamoto T (2010) Pivotal advance: interconversion between pure chemotactic ligands and chemoattractant/secretagogue ligands of neutrophil C5a receptor by a single amino acid substitution. J Leukoc Biol 87:965–975CrossRefGoogle Scholar
  12. Laudes IJ, Chu JC, Huber-Lang M, Guo RF, Riedemann NC, Sarma JV, Mahdi F, Murphy HS, Speyer C, Lu KT et al (2002) Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol 169:5962–5970CrossRefGoogle Scholar
  13. Lee JS, Yang EJ, Kim IS (2009) The roles of MCP-1 and protein kinase C delta activation in human eosinophilic ­leukemia EoL-1 cells. Cytokine 48:186–195CrossRefGoogle Scholar
  14. Lo RK, Cheung H, Wong YH (2003) Constitutively active Galpha16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. J Biol Chem 278:52154–52165CrossRefGoogle Scholar
  15. Monk PN, Scola AM, Madala P, Fairlie DP (2007) Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol 152:429–448CrossRefGoogle Scholar
  16. Mullick A, Tremblay J, Leon Z, Gros P (2011) A novel role for the fifth component of complement (C5) in cardiac physiology. PLoS One 6:e22919CrossRefGoogle Scholar
  17. Murai N, Nagai K, Fujisawa H, Hatanaka K, Kawamura M, Harada Y (2003) Concurrent evolution and resolution in an acute inflammatory model of rat carrageenan-induced pleurisy. J Leukoc Biol 73:456–463CrossRefGoogle Scholar
  18. Nishimura T, Horino K, Nishiura H, Shibuya Y, Hiraoka T, Tanase S, Yamamoto T (2001) Apoptotic cells of an epithelial cell line, AsPC-1, release monocyte chemotactic S19 ribosomal protein dimer. J Biochem 129:445–454CrossRefGoogle Scholar
  19. Nishiura H, Shibuya Y, Yamamoto T (1998) S19 ribosomal protein cross-linked dimer causes monocyte-predominant infiltration by means of molecular mimicry to complement C5a. Lab Invest 78:1615–1623PubMedGoogle Scholar
  20. Nishiura H, Tanase S, Sibuya Y, Nishimura T, Yamamoto T (1999) Determination of the cross-linked residues in homo-dimerization of S19 ribosomal protein concomitant with exhibition of monocyte chemotactic activity. Lab Invest 79:915–923PubMedGoogle Scholar
  21. Nishiura H, Tanase S, Shibuya Y, Futa N, Sakamoto T, Higginbottom A, Monk P, Zwirner J, Yamamoto T (2005) S19 ribosomal protein dimer augments metal-induced apoptosis in a mouse fibroblastic cell line by ligation of the C5a receptor. J Cell Biochem 94:540–553CrossRefGoogle Scholar
  22. Nishiura H, Nonaka H, Revollo IS, Semba U, Li Y, Ota Y, Irie A, Harada K, Kehrl JH, 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. Lab Invest 89:676–694CrossRefGoogle Scholar
  23. Nishiura H, Chen J, Ota Y, Semba U, Higuchi H, Nakashima T, Yamamoto T (2010) Base of molecular mimicry between human ribosomal protein S19 dimer and human C5a anaphylatoxin. Int Immunopharmacol 10:1541–1547CrossRefGoogle Scholar
  24. Nishiura H, Tanase S, Tsujita K, Sugiyama S, Ogawa H, Nakagaki T, Semba U, Yamamoto T (2011) Maintenance of ribosomal protein S19 in plasma by complex formation with prothrombin. Eur J Haematol 86:436–441CrossRefGoogle Scholar
  25. Oda Y, Tokita K, Ota Y, Li Y, Taniguchi K, Nishino N, Takagi K, Yamamoto T, 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. J Biochem 144:371–381CrossRefGoogle Scholar
  26. Ota Y, Chen J, Shin M, Nishiura H, Tokita K, Shinohara M, Yamamoto T (2010) Role of ribosomal protein S19-like plasma protein in blood coagulum resorption. Exp Mol Pathol 90:19–28CrossRefGoogle Scholar
  27. Revollo I, Nishiura H, Shibuya Y, Oda Y, Nishino N, Yamamoto T (2005) Agonist and antagonist dual effect of the cross-linked S19 ribosomal protein dimer in the C5a receptor-mediated respiratory burst reaction of phagocytic leukocytes. Inflamm Res 54:82–90CrossRefGoogle Scholar
  28. Semba U, Chen J, Ota Y, Jia N, Arima H, Nishiura H, Yamamoto T (2010) A plasma protein indistinguishable from ribosomal protein S19: conversion to a monocyte chemotactic factor by a factor XIIIa-catalyzed reaction on activated platelet membrane phosphatidylserine in association with blood coagulation. Am J Pathol 176:1542–1551CrossRefGoogle Scholar
  29. Shibuya Y, Shiokawa M, Nishiura H, Nishimura T, Nishino N, Okabe H, Takagi K, Yamamoto T (2001) Identification of receptor-binding sites of monocyte chemotactic S19 ribosomal protein dimer. Am J Pathol 159:2293–2301CrossRefGoogle Scholar
  30. Shrestha A, Shiokawa M, Nishimura T, Nishiura H, Tanaka Y, Nishino N, Shibuya Y, Yamamoto T (2003) Switch moiety in agonist/antagonist dual effect of S19 ribosomal protein dimer on leukocyte chemotactic C5a receptor. Am J Pathol 162:1381–1388CrossRefGoogle Scholar
  31. Snyderman R, Phillips JK, Mergenhagen SE (1971) Biological activity of complement in vivo. Role of C5 in the accumulation of polymorphonuclear leukocytes in inflammatory exudates. J Exp Med 134:1131–1143CrossRefGoogle Scholar
  32. Woodruff TM, Nandakumar KS, Tedesco F (2011) Inhibiting the C5–C5a receptor axis. Mol Immunol 48:1631–1642CrossRefGoogle Scholar
  33. Zhang C, Xu R, Wang J, Han G, Chen G, Wang R, Wei H, Shen B, Ma Y, Li Y (2007) Functional identification of the stable transfection C5aR cell line Molt-4. Cell Mol Immunol 4:461–465PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Molecular PathologyKumamoto University Graduate SchoolKumamotoJapan

Personalised recommendations