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The Role of Complement C3a Receptor in Stroke

  • Saif AhmadEmail author
  • Kanchan Bhatia
  • Adam Kindelin
  • Andrew F. DucruetEmail author
Review Paper
  • 43 Downloads

Abstract

The complement system is a key regulator of the innate immune response against diseased tissue that functions across multiple organ systems. Dysregulation of complement contributes to the pathogenesis of a number of neurological diseases including stroke. The C3a anaphylatoxin, via its cognate C3a receptor (C3aR), mediates inflammation by promoting breakdown of the blood–brain barrier and the massive infiltration of leukocytes into ischemic brain in experimental stroke models. Studies utilizing complement deficient mice as well as pharmacologic C3aR antagonists have shown a reduction in tissue injury and mortality in murine stroke models. The development of tissue-specific C3aR knockout mice and more specific C3aR antagonists is warranted to facilitate our understanding of the role of the C3aR in brain ischemia with the ultimate goal of clinical translation of therapies targeting C3aR in stroke patients.

Keywords

Complement cascade Central nervous system Stroke C3a receptor C3a receptor antagonist 

Notes

Acknowledgements

Research in the authors’s lab is funded by the Barrow Neurological Foundation. The authors thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with figure preparation. We thank to Ms. Tasha Mohseni for her editorial assistance with manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Ames, R. S., Lee, D., Foley, J. J., Jurewicz, A. J., Tornetta, M. A., Bautsch, W., et al. (2001). Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. Journal of Immunology, 166(10), 6341–6348.Google Scholar
  2. Ames, R. S., Li, Y., Sarau, H. M., Nuthulaganti, P., Foley, J. J., Ellis, C., et al. (1996). Molecular cloning and characterization of the human anaphylatoxin C3a receptor. Journal of Biological Chemistry, 271(34), 20231–20234.Google Scholar
  3. Arumugam, T. V., Woodruff, T. M., Lathia, J. D., Selvaraj, P. K., Mattson, M. P., & Taylor, S. M. (2009). Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience, 158(3), 1074–1089.  https://doi.org/10.1016/j.neuroscience.2008.07.015.Google Scholar
  4. Barnum, S. R., Ames, R. S., Maycox, P. R., Hadingham, S. J., Meakin, J., Harrison, D., et al. (2002). Expression of the complement C3a and C5a receptors after permanent focal ischemia: An alternative interpretation. Glia, 38(2), 169–173.Google Scholar
  5. Beatty, W. K., & Beatty, V. L. (1975). Medical school libraries in the United States and Canada built between 1961 and 1971. Bulletin of the Medical Library Association, 63(3), 324–336.Google Scholar
  6. Benjamin, E. J., Blaha, M. J., Chiuve, S. E., Cushman, M., Das, S. R., Deo, R., et al. (2017). Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation, 135(10), e146–e603.  https://doi.org/10.1161/cir.0000000000000485.Google Scholar
  7. Blatt, A. Z., Pathan, S., & Ferreira, V. P. (2016). Properdin: A tightly regulated critical inflammatory modulator. Immunological Reviews, 274(1), 172–190.  https://doi.org/10.1111/imr.12466.Google Scholar
  8. Bogestal, Y. R., Barnum, S. R., Smith, P. L., Mattisson, V., Pekny, M., & Pekna, M. (2007). Signaling through C5aR is not involved in basal neurogenesis. Journal of Neuroscience Research, 85(13), 2892–2897.  https://doi.org/10.1002/jnr.21401.Google Scholar
  9. Boos, L., Szalai, A. J., & Barnum, S. R. (2005). C3a expressed in the central nervous system protects against LPS-induced shock. Neuroscience Letters, 387(2), 68–71.  https://doi.org/10.1016/j.neulet.2005.07.015.Google Scholar
  10. Caporale, L. H., Tippett, P. S., Erickson, B. W., & Hugli, T. E. (1980). The active site of C3a anaphylatoxin. Journal of Biological Chemistry, 255(22), 10758–10763.Google Scholar
  11. Carpanini, S. M., Torvell, M., & Morgan, B. P. (2019). Therapeutic inhibition of the complement system in diseases of the central nervous system. Frontiers in Immunology, 10, 362.  https://doi.org/10.3389/fimmu.2019.00362.Google Scholar
  12. Chao, T. H., Ember, J. A., Wang, M., Bayon, Y., Hugli, T. E., & Ye, R. D. (1999). Role of the second extracellular loop of human C3a receptor in agonist binding and receptor function. Journal of Biological Chemistry, 274(14), 9721–9728.Google Scholar
  13. Chen, Y., Tsai, Y. H., & Tseng, S. H. (2011). The potential of tetrandrine as a protective agent for ischemic stroke. Molecules, 16(9), 8020–8032.  https://doi.org/10.3390/molecules16098020.Google Scholar
  14. Crass, T., Ames, R. S., Sarau, H. M., Tornetta, M. A., Foley, J. J., Kohl, J., et al. (1999). Chimeric receptors of the human C3a receptor and C5a receptor (CD88). Journal of Biological Chemistry, 274(13), 8367–8370.Google Scholar
  15. Dando, S. J., Mackay-Sim, A., Norton, R., Currie, B. J., St John, J. A., Ekberg, J. A., et al. (2014). Pathogens penetrating the central nervous system: Infection pathways and the cellular and molecular mechanisms of invasion. Clinical Microbiology Reviews, 27(4), 691–726.  https://doi.org/10.1128/CMR.00118-13.Google Scholar
  16. Daneman, R., & Prat, A. (2015). The blood-brain barrier. Cold Spring Harbor Perspectives in Biology, 7(1), a020412.  https://doi.org/10.1101/cshperspect.a020412.Google Scholar
  17. Davoust, N., Jones, J., Stahel, P. F., Ames, R. S., & Barnum, S. R. (1999). Receptor for the C3a anaphylatoxin is expressed by neurons and glial cells. Glia, 26(3), 201–211.Google Scholar
  18. de Vries, B., Walter, S. J., Peutz-Kootstra, C. J., Wolfs, T. G., van Heurn, L. W., & Buurman, W. A. (2004). The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury. American Journal of Pathology, 165(5), 1677–1688.  https://doi.org/10.1016/S0002-9440(10)63424-4.Google Scholar
  19. Ducruet, A. F., Hassid, B. G., Mack, W. J., Sosunov, S. A., Otten, M. L., Fusco, D. J., et al. (2008). C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. Journal of Cerebral Blood Flow and Metabolism, 28(5), 1048–1058.  https://doi.org/10.1038/sj.jcbfm.9600608.Google Scholar
  20. Ducruet, A. F., Zacharia, B. E., Hickman, Z. L., Grobelny, B. T., Yeh, M. L., Sosunov, S. A., et al. (2009). The complement cascade as a therapeutic target in intracerebral hemorrhage. Experimental Neurology, 219(2), 398–403.  https://doi.org/10.1016/j.expneurol.2009.07.018.Google Scholar
  21. Ducruet, A. F., Zacharia, B. E., Sosunov, S. A., Gigante, P. R., Yeh, M. L., Gorski, J. W., et al. (2012). Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS ONE, 7(6), e38664.  https://doi.org/10.1371/journal.pone.0038664.Google Scholar
  22. Ehlers, M. R. (2000). CR22: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes and Infection, 2(3), 289–294.Google Scholar
  23. Gravanis, I., & Tsirka, S. E. (2008). Tissue-type plasminogen activator as a therapeutic target in stroke. Expert Opinion on Therapeutic Targets, 12(2), 159–170.  https://doi.org/10.1517/14728222.12.2.159.Google Scholar
  24. Heurich, B., El Idrissi, N. B., Donev, R. M., Petri, S., Claus, P., Neal, J., et al. (2011). Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. Journal of Neuroimmunology, 235(1–2), 104–109.  https://doi.org/10.1016/j.jneuroim.2011.03.011.Google Scholar
  25. Jacob, A., & Alexander, J. J. (2014). Complement and blood-brain barrier integrity. Molecular Immunology, 61(2), 149–152.  https://doi.org/10.1016/j.molimm.2014.06.039.Google Scholar
  26. Jarlestedt, K., Rousset, C. I., Stahlberg, A., Sourkova, H., Atkins, A. L., Thornton, C., et al. (2013). Receptor for complement peptide C3a: A therapeutic target for neonatal hypoxic-ischemic brain injury. The FASEB Journal, 27(9), 3797–3804.  https://doi.org/10.1096/fj.13-230011.Google Scholar
  27. Jauneau, A. C., Ischenko, A., Chatagner, A., Benard, M., Chan, P., Schouft, M. T., et al. (2006). Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. Journal of Neuroinflammation, 3, 8.  https://doi.org/10.1186/1742-2094-3-8.Google Scholar
  28. Jin, K., Minami, M., Lan, J. Q., Mao, X. O., Batteur, S., Simon, R. P., et al. (2001). Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proceedings of the National Academy of Sciences of the United States of America, 98(8), 4710–4715.  https://doi.org/10.1073/pnas.081011098.Google Scholar
  29. Kalogeris, T., Baines, C. P., Krenz, M., & Korthuis, R. J. (2012). Cell biology of ischemia/reperfusion injury. International Review of Cell and Molecular Biology, 298, 229–317.  https://doi.org/10.1016/B978-0-12-394309-5.00006-7.Google Scholar
  30. Lacy, M., Jones, J., Whittemore, S. R., Haviland, D. L., Wetsel, R. A., & Barnum, S. R. (1995). Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and FMLP by human astrocytes and microglia. Journal of Neuroimmunology, 61(1), 71–78.Google Scholar
  31. Leblhuber, F., Walli, J., Jellinger, K., Tilz, G. P., Widner, B., Laccone, F., et al. (1998). Activated immune system in patients with Huntington’s disease. Clinical Chemistry and Laboratory Medicine, 36(10), 747–750.  https://doi.org/10.1515/CCLM.1998.132.Google Scholar
  32. Liu, S., Feng, X., Jin, R., & Li, G. (2018). Tissue plasminogen activator-based nanothrombolysis for ischemic stroke. Expert Opinion on Drug Delivery, 15(2), 173–184.  https://doi.org/10.1080/17425247.2018.1384464.Google Scholar
  33. Lohman, R. J., Hamidon, J. K., Reid, R. C., Rowley, J. A., Yau, M. K., Halili, M. A., et al. (2017). Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a. Nature Communications, 8(1), 351.  https://doi.org/10.1038/s41467-017-00414-w.Google Scholar
  34. Martin, U., Bock, D., Arseniev, L., Tornetta, M. A., Ames, R. S., Bautsch, W., et al. (1997). The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes. Journal of Experimental Medicine, 186(2), 199–207.Google Scholar
  35. Mathieu, M. C., Sawyer, N., Greig, G. M., Hamel, M., Kargman, S., Ducharme, Y., et al. (2005). The C3a receptor antagonist SB 290157 has agonist activity. Immunology Letters, 100(2), 139–145.  https://doi.org/10.1016/j.imlet.2005.03.003.Google Scholar
  36. Merle, N. S., Church, S. E., Fremeaux-Bacchi, V., & Roumenina, L. T. (2015). Complement system part I—Molecular mechanisms of activation and regulation. Frontiers in Immunology, 6, 262.  https://doi.org/10.3389/fimmu.2015.00262.Google Scholar
  37. Miller, D. J., Simpson, J. R., & Silver, B. (2011). Safety of thrombolysis in acute ischemic stroke: A review of complications, risk factors, and newer technologies. Neurohospitalist, 1(3), 138–147.  https://doi.org/10.1177/1941875211408731.Google Scholar
  38. Mocco, J., Wilson, D. A., Komotar, R. J., Sughrue, M. E., Coates, K., Sacco, R. L., et al. (2006). Alterations in plasma complement levels after human ischemic stroke. Neurosurgery, 59(1), 28–33.  https://doi.org/10.1227/01.neu.0000219221.14280.65. (discussion 28–33).Google Scholar
  39. Mollnes, T. E., Song, W. C., & Lambris, J. D. (2002). Complement in inflammatory tissue damage and disease. Trends in Immunology, 23(2), 61–64.Google Scholar
  40. Morgan, B. P. (2018). Complement in the pathogenesis of Alzheimer’s disease. Seminars in Immunopathology, 40(1), 113–124.  https://doi.org/10.1007/s00281-017-0662-9.Google Scholar
  41. Norgauer, J., Dobos, G., Kownatzki, E., Dahinden, C., Burger, R., Kupper, R., et al. (1993). Complement fragment C3a stimulates Ca2+ influx in neutrophils via a pertussis-toxin-sensitive G protein. European Journal of Biochemistry, 217(1), 289–294.Google Scholar
  42. Noris, M., & Remuzzi, G. (2013). Overview of complement activation and regulation. Seminars in Nephrology, 33(6), 479–492.  https://doi.org/10.1016/j.semnephrol.2013.08.001.Google Scholar
  43. O’Barr, S. A., Caguioa, J., Gruol, D., Perkins, G., Ember, J. A., Hugli, T., et al. (2001). Neuronal expression of a functional receptor for the C5a complement activation fragment. Journal of Immunology, 166(6), 4154–4162.Google Scholar
  44. Pfisterer, U., & Khodosevich, K. (2017). Neuronal survival in the brain: Neuron type-specific mechanisms. Cell Death & Disease, 8(3), e2643.  https://doi.org/10.1038/cddis.2017.64.Google Scholar
  45. Rahpeymai, Y., Hietala, M. A., Wilhelmsson, U., Fotheringham, A., Davies, I., Nilsson, A. K., et al. (2006). Complement: A novel factor in basal and ischemia-induced neurogenesis. EMBO Journal, 25(6), 1364–1374.  https://doi.org/10.1038/sj.emboj.7601004.Google Scholar
  46. Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016). The indispensable roles of microglia and astrocytes during brain development. Frontiers in Human Neuroscience, 10, 566.  https://doi.org/10.3389/fnhum.2016.00566.Google Scholar
  47. Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D. (2010). Complement: A key system for immune surveillance and homeostasis. Nature Immunology, 11(9), 785–797.  https://doi.org/10.1038/ni.1923.Google Scholar
  48. Schafer, M. K., Schwaeble, W. J., Post, C., Salvati, P., Calabresi, M., Sim, R. B., et al. (2000). Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia. Journal of Immunology, 164(10), 5446–5452.Google Scholar
  49. Settmacher, B., Rheinheimer, C., Hamacher, H., Ames, R. S., Wise, A., Jenkinson, L., et al. (2003). Structure-function studies of the C3a-receptor: C-terminal serine and threonine residues which influence receptor internalization and signaling. European Journal of Immunology, 33(4), 920–927.  https://doi.org/10.1002/eji.200323293.Google Scholar
  50. Shen, Y., Li, R., McGeer, E. G., & McGeer, P. L. (1997). Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain. Brain Research, 769(2), 391–395.Google Scholar
  51. Shinjyo, N., Stahlberg, A., Dragunow, M., Pekny, M., & Pekna, M. (2009). Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells, 27(11), 2824–2832.  https://doi.org/10.1002/stem.225.Google Scholar
  52. Sochocka, M., Diniz, B. S., & Leszek, J. (2017). Inflammatory response in the CNS: Friend or foe? Molecular Neurobiology, 54(10), 8071–8089.  https://doi.org/10.1007/s12035-016-0297-1.Google Scholar
  53. Stokowska, A., Atkins, A. L., Moran, J., Pekny, T., Bulmer, L., Pascoe, M. C., et al. (2017). Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia. Brain, 140(2), 353–369.  https://doi.org/10.1093/brain/aww314.Google Scholar
  54. Sun, Y., Jin, K., Xie, L., Childs, J., Mao, X. O., Logvinova, A., et al. (2003). VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. Journal of Clinical Investigation, 111(12), 1843–1851.  https://doi.org/10.1172/JCI17977.Google Scholar
  55. Therien, A. G. (2005). Agonist activity of the small molecule C3aR ligand SB 290157. Journal of Immunology, 174(12), 7479. (author reply 7479–7480).Google Scholar
  56. Thomas, A., Gasque, P., Vaudry, D., Gonzalez, B., & Fontaine, M. (2000). Expression of a complete and functional complement system by human neuronal cells in vitro. International Immunology, 12(7), 1015–1023.Google Scholar
  57. Thurman, J. M., & Holers, V. M. (2006). The central role of the alternative complement pathway in human disease. Journal of Immunology, 176(3), 1305–1310.Google Scholar
  58. Tornetta, M. A., Foley, J. J., Sarau, H. M., & Ames, R. S. (1997). The mouse anaphylatoxin C3a receptor: Molecular cloning, genomic organization, and functional expression. Journal of Immunology, 158(11), 5277–5282.Google Scholar
  59. Van Beek, J., Bernaudin, M., Petit, E., Gasque, P., Nouvelot, A., MacKenzie, E. T., et al. (2000). Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in the mouse. Experimental Neurology, 161(1), 373–382.  https://doi.org/10.1006/exnr.1999.7273.Google Scholar
  60. Vasek, M. J., Garber, C., Dorsey, D., Durrant, D. M., Bollman, B., Soung, A., et al. (2016). A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature, 534(7608), 538–543.  https://doi.org/10.1038/nature18283.Google Scholar
  61. Veerhuis, R., Janssen, I., De Groot, C. J., Van Muiswinkel, F. L., Hack, C. E., & Eikelenboom, P. (1999). Cytokines associated with amyloid plaques in Alzheimer’s disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor. Experimental Neurology, 160(1), 289–299.  https://doi.org/10.1006/exnr.1999.7199.Google Scholar
  62. Veerhuis, R., Nielsen, H. M., & Tenner, A. J. (2011). Complement in the brain. Molecular Immunology, 48(14), 1592–1603.  https://doi.org/10.1016/j.molimm.2011.04.003.Google Scholar
  63. Walker, D. G., Kim, S. U., & McGeer, P. L. (1998). Expression of complement C4 and C9 genes by human astrocytes. Brain Res, 809(1), 31–38.Google Scholar
  64. Wang, Y., Hancock, A. M., Bradner, J., Chung, K. A., Quinn, J. F., Peskind, E. R., et al. (2011). Complement 3 and factor h in human cerebrospinal fluid in Parkinson’s disease, Alzheimer’s disease, and multiple-system atrophy. American Journal of Pathology, 178(4), 1509–1516.  https://doi.org/10.1016/j.ajpath.2011.01.006.Google Scholar
  65. Woodruff, T. M., Ager, R. R., Tenner, A. J., Noakes, P. G., & Taylor, S. M. (2010). The role of the complement system and the activation fragment C5a in the central nervous system. Neuromolecular Medicine, 12(2), 179–192.  https://doi.org/10.1007/s12017-009-8085-y.Google Scholar
  66. Woodruff, T. M., Thundyil, J., Tang, S. C., Sobey, C. G., Taylor, S. M., & Arumugam, T. V. (2011). Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Molecular Neurodegeneration, 6(1), 11.  https://doi.org/10.1186/1750-1326-6-11.Google Scholar
  67. Xiong, C., Liu, J., Lin, D., Zhang, J., Terrando, N., & Wu, A. (2018). Complement activation contributes to perioperative neurocognitive disorders in mice. Journal of Neuroinflammation, 15(1), 254.  https://doi.org/10.1186/s12974-018-1292-4.Google Scholar
  68. Yanamadala, V., & Friedlander, R. M. (2010). Complement in neuroprotection and neurodegeneration. Trends in Molecular Medicine, 16(2), 69–76.  https://doi.org/10.1016/j.molmed.2009.12.001.Google Scholar
  69. Zhao, X. J., Larkin, T. M., Lauver, M. A., Ahmad, S., & Ducruet, A. F. (2017). Tissue plasminogen activator mediates deleterious complement cascade activation in stroke. PLoS ONE, 12(7), e0180822.  https://doi.org/10.1371/journal.pone.0180822.Google Scholar

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Authors and Affiliations

  1. 1.Department of Neurosurgery, Barrow Neurological InstituteSt. Joseph’s Hospital and Medical Center (SJHMC), Dignity HealthPhoenixUSA
  2. 2.School of Mathematical and Natural SciencesArizona State UniversityPhoenixUSA

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