The Role of Complement C3a Receptor in Stroke

Overview

Journal Neuromolecular Med

Specialty Biochemistry

Date 2019 May 19

PMID 31102134

Citations 7

Authors

Saif Ahmad

Kanchan Bhatia

Adam Kindelin

Andrew F Ducruet

Affiliations

Soon will be listed here.

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.

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References

Thomas A, Gasque P, Vaudry D, Gonzalez B, Fontaine M . Expression of a complete and functional complement system by human neuronal cells in vitro. Int Immunol. 2000; 12(7):1015-23. DOI: 10.1093/intimm/12.7.1015. View

Ehlers M . CR3: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes Infect. 2000; 2(3):289-94. DOI: 10.1016/s1286-4579(00)00299-9. View

Boos L, Szalai A, Barnum S . C3a expressed in the central nervous system protects against LPS-induced shock. Neurosci Lett. 2005; 387(2):68-71. DOI: 10.1016/j.neulet.2005.07.015. View

Norgauer J, Dobos G, Kownatzki E, Dahinden C, Burger R, KUPPER R . Complement fragment C3a stimulates Ca2+ influx in neutrophils via a pertussis-toxin-sensitive G protein. Eur J Biochem. 1993; 217(1):289-94. DOI: 10.1111/j.1432-1033.1993.tb18245.x. View

Veerhuis R, Nielsen H, Tenner A . Complement in the brain. Mol Immunol. 2011; 48(14):1592-603. PMC: 3142281. DOI: 10.1016/j.molimm.2011.04.003. View

Caporale L, Tippett P, Erickson B, Hugli T . The active site of C3a anaphylatoxin. J Biol Chem. 1980; 255(22):10758-63. View

Rahpeymai Y, Hietala M, Wilhelmsson U, Fotheringham A, Davies I, Nilsson A . Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006; 25(6):1364-74. PMC: 1422160. DOI: 10.1038/sj.emboj.7601004. View

Crass T, Ames R, Sarau H, Tornetta M, FOLEY J, Kohl J . Chimeric receptors of the human C3a receptor and C5a receptor (CD88). J Biol Chem. 1999; 274(13):8367-70. DOI: 10.1074/jbc.274.13.8367. View

Carpanini S, Torvell M, Morgan B . Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Front Immunol. 2019; 10:362. PMC: 6409326. DOI: 10.3389/fimmu.2019.00362. View

10.

Dando S, Mackay-Sim A, Norton R, Currie B, St John J, Ekberg J . Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin Microbiol Rev. 2014; 27(4):691-726. PMC: 4187632. DOI: 10.1128/CMR.00118-13. View

11.

Therien A . Agonist activity of the small molecule C3aR ligand SB 290157. J Immunol. 2005; 174(12):7479. DOI: 10.4049/jimmunol.174.12.7479. View

12.

Mollnes T, Song W, Lambris J . Complement in inflammatory tissue damage and disease. Trends Immunol. 2002; 23(2):61-4. DOI: 10.1016/s1471-4906(01)02129-9. View

13.

Morgan B . Complement in the pathogenesis of Alzheimer's disease. Semin Immunopathol. 2017; 40(1):113-124. PMC: 5794825. DOI: 10.1007/s00281-017-0662-9. View

14.

Sun Y, Jin K, Xie L, Childs J, Mao X, Logvinova A . VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003; 111(12):1843-51. PMC: 161428. DOI: 10.1172/JCI17977. View

15.

Lacy M, Jones J, Whittemore S, Haviland D, Wetsel R, Barnum S . Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and FMLP by human astrocytes and microglia. J Neuroimmunol. 1995; 61(1):71-8. DOI: 10.1016/0165-5728(95)00075-d. View

16.

van Beek J, Bernaudin M, Petit E, Gasque P, Nouvelot A, MacKenzie E . Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in the mouse. Exp Neurol. 2000; 161(1):373-82. DOI: 10.1006/exnr.1999.7273. View

17.

OBarr S, Caguioa J, Gruol D, Perkins G, Ember J, Hugli T . Neuronal expression of a functional receptor for the C5a complement activation fragment. J Immunol. 2001; 166(6):4154-62. DOI: 10.4049/jimmunol.166.6.4154. View

18.

Jauneau A, Ischenko A, Chatagner A, Benard M, Chan P, Schouft M . Interleukin-1beta and anaphylatoxins exert a synergistic effect on NGF expression by astrocytes. J Neuroinflammation. 2006; 3:8. PMC: 1482689. DOI: 10.1186/1742-2094-3-8. View

19.

Ducruet A, Hassid B, Mack W, Sosunov S, Otten M, Fusco D . C3a receptor modulation of granulocyte infiltration after murine focal cerebral ischemia is reperfusion dependent. J Cereb Blood Flow Metab. 2008; 28(5):1048-58. DOI: 10.1038/sj.jcbfm.9600608. View

20.

Vasek M, Garber C, Dorsey D, Durrant D, Bollman B, Soung A . A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016; 534(7608):538-43. PMC: 5452615. DOI: 10.1038/nature18283. View