Complement component 5a (C5a)

School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 05/2009; 41(11):2114-7. DOI: 10.1016/j.biocel.2009.04.005
Source: PubMed


The 74 amino acid glycoprotein, complement component 5a (C5a), is a potent pro-inflammatory mediator cleaved enzymatically from its precursor, C5, upon activation of the complement cascade. C5a is quickly metabolised by carboxypeptidases, forming the less potent C5adesArg. Acting via a classical G protein-coupled receptor, CD88, C5a and C5adesArg exert a number of effects essential to the innate immune response, while their actions at the more recently discovered non-G protein-coupled receptor, C5L2 (or GPR77), remain unclear. The widespread expression of C5a receptors throughout the body allows C5a to elicit a broad range of effects. Thus, C5a has been found to be a significant pathogenic driver in a number of immuno-inflammatory diseases, making C5a inhibition an attractive therapeutic strategy.

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    • "C5a also interacts with a second receptor, C5a 2 , although the functions of this receptor are not fully determined (Croker et al., 2013; Li et al., 2013). Increased amounts of C5a are associated with a number of pathological conditions, including lupus, ischemia/reperfusion injury, Crohn's disease, cystic fibrosis, gingivitis, atherosclerosis, myocardial infarction, fibrosis, allergy, diabetes type I, and disorders of the central nervous system (Manthey et al., 2009). Inhibition of C3a and C5a interactions with their respective receptors, C3a receptor and C5a 1 , has been targeted for drug design (Bellows-Peterson et al., 2012; Monk et al., 2007). "
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    ABSTRACT: The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena.
    European Journal of Pharmacology 10/2014; 745. DOI:10.1016/j.ejphar.2014.10.041 · 2.53 Impact Factor
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    • "It can be activated following infection or injury through four distinct pathways, which lead to opsonisation of pathogens, cell lysis, and the production of potent pro-inflammatory peptides. The complement protein C5a is generated following cleavage of the 5th component of complement (C5), and is one of the most potent inflammatory mediators in humans [1]. Given its potent inflammatory activity, prolonged or inappropriate activation of complement can generate unwanted C5a, which is implicated in many inflammatory diseases [2,3]. "
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    ABSTRACT: Background The complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease. Results We construct for the first time molecular models for the C5aR:PMX53 complex without the a priori use of experimental constraints, via a computational framework of molecular dynamics (MD) simulations, docking, conformational clustering and free energy filtering. The models agree with experimental data, and are used to propose important intermolecular interactions contributing to binding, and to develop a hypothesis for the mechanism of PMX53 antagonism. Conclusion This work forms the basis for the design of improved C5aR antagonists, as well as for atomic-detail mechanistic studies of complement activation and function. Our computational framework can be widely used to develop GPCR-ligand structural models in membrane environments, peptidomimetics and other chemical compounds with potential clinical use.
    BMC Biophysics 08/2014; 7(1):5. DOI:10.1186/2046-1682-7-5 · 2.89 Impact Factor
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    • "C5a is an anaphylatoxin liberated from the N-terminal region of the parental protein α-chain and is similar in molecular structure (2). C5a is a potent soluble anaphylotoxic and chemotactic inflammatory mediator promoting the recruitment and activation of neutrophils and monocytes/macrophages (15). C5a acts on numerous types of cells by binding to the C5aR receptor and causes proinflammatory activation (3,16). "
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    ABSTRACT: Receptor binding of complement anaphylatoxin C5a results in proinflammatory activation of numerous diseases, but the role of receptor-mediated action during hyperoxic lung injury has, to the best of our knowledge, not yet been investigated. The contribution of the C5a receptor (C5aR) to hyperoxic lung injury in mice was investigated in this study. The effect of C5aR on hyperoxic lung injury in Balb/c mice was examined employing a C5aR antagonist (C5aRA). The mice were ventilated with 100% oxygen for 36 h with or without the administration of C5aRA. C5aR expression levels in non‑treated or 100% oxygen‑treated mice were assessed by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The body weight and the relative lung weight of the mice, and the morphological changes in the lung were then determined. The total cell counts and the number of macrophages, neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) were determined using cytocentrifuge slides and a hemocytometer. The levels of interleukin-6 (IL-6), monocyte chemotactic protein (MCP-1) and tumor necrosis factor-α (TNF-α) in BALF and the myeloperoxidase (MPO) activity in the lung tissue were measured by enzyme-linked immunosorbent assay. The relative levels of CD68 and F4/80 messenger ribonucleic acid (mRNA) expression in the lung tissue were detected by RT-PCR. The TNF-α, IL-6 and MCP-1 protein expression levels in the lung tissue were assessed by western blot analysis. The results revealed hyperoxia-induced morphological changes, lung injury and increased expression levels of C5aR in lung tissue. The hyperoxia‑induced increases in the total cell count and the number of macrophages, neutrophils and lymphocytes in the BALF were all significantly reduced in the mice receiving C5aRA. Treatment with C5aRA also attenuated the morphological changes and reduced MPO activity, and CD68 and F4/80 mRNA expression levels in the lung tissue, as well as the levels of IL-6, MCP-1 and TNF-α in BALF and lung tissue. In conclusion, C5a-C5aR action accelerated hyperoxia-induced lung injury, but this hyperoxic lung injury was attenuated by treatment with C5aRA.
    Molecular Medicine Reports 07/2014; 10(4). DOI:10.3892/mmr.2014.2394 · 1.55 Impact Factor
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