Complement component 5a

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complement component 5
C5a-3D.png
Schematic representation of three-dimensional structure of complement 5a
Identifiers
SymbolC5
NCBI gene 727
HGNC 1331
OMIM 120900
RefSeq NM_001735
UniProt P01031
Other data
Locus Chr. 9 q34.1
Search for
Structures Swiss-model
Domains InterPro

C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the membrane attack complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases. [1]

Contents

Structure

Human polypeptide C5a contains 74 amino acids and has 11kDa. NMR spectroscopy proved that the molecule is composed of four helices and connected by peptide loops with three disulphide bonds between helix IV and II, III. There is a short 1.5 turn helix on N-terminus but all agonist activity take place in the C-terminus. C5a is rapidly metabolised by a serum enzyme carboxypeptidase B to a 72 amino acid form C5a des-Arg without C terminal arginine. [2] [3]

Functions

C5a is an anaphylatoxin, causing increased expression of adhesion molecules on endothelium, contraction of smooth muscle, and increased vascular permeability. C5a des-Arg is a much less potent anaphylatoxin. Both C5a and C5a des-Arg can trigger mast cell degranulation, releasing proinflammatory molecules histamine and TNF-α. C5a is also an effective chemoattractant, [4] initiating accumulation of complement and phagocytic cells at sites of infection or recruitment of antigen-presenting cells to lymph nodes. [5] C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of integrin avidity, the lipoxygenase pathway and arachidonic acid metabolism. C5a also modulates the balance between activating versus inhibitory IgG Fc receptors on leukocytes, thereby enhancing the autoimmune response. [1]

Binding process

C5a interact with receptor protein C5a Receptor 1 (C5aR1) on the surface of target cells such as macrophages, neutrophils and endothelial cells. C5aR1 is a member of the G-protein-coupled receptor superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic amino acid residues, forming three intra- and three extra-cellular loops, with an extracellular N-terminus and an intracellular C-terminus.

C5a binding to the receptor is a two-stage process: an interaction between basic residues in the helical core of C5a and acidic residues in the extracellular N-terminal domain allows the C-terminus of C5a to bind to residues in the receptor transmembrane domains. The latter interaction leads to receptor activation, and the transduction of the ligand binding signal across the cell plasma membrane to the cytoplasmic G protein Gi type GNAI2. [6]

Sensitivity of C5aR1 to C5a stimulation is enhanced by lipopolysaccharides exposure. C5a, acting via C5aR1, is shown to differentially modulate lipopolysaccharides-induced inflammatory responses in primary human monocytes versus macrophages, [7] yet this is not due to C5aR1 upregulation. [8] C5L2 is another C5a receptor that is thought to regulate the C5a-C5aR1 effects. There is apparently contradictory evidence showing decoy receptor activity conferring anti-inflammatory properties and also signalling activity conferring pro-inflammatory properties. [9] [1]

Diseases

C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases involving the complement system such as sepsis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythemotosis, psoriasis. The inhibitor of C5a that can block its effects would be helpful in medical applications. Another candidate is PMX53 or PMX205 that is highly specific for CD88 and effectively reduces inflammatory response. [10] [11] C5a has been identified as a key mediator of neutrophil dysfunction in sepsis, with antibody blockade of C5a improving outcomes in experimental models. [12] This has also been shown in humans, [13] with C5a-mediated neutrophil dysfunction predicting subsequent nosocomial infection [14] [15] and death from sepsis. [16] [17] Recent data demonstrates that C5a not only impairs phagocytosis by neutrophils but also impairs phagosomal maturation, [18] inducing a marked alteration in the neutrophil phosphoproteomic response to bacterial targets. C5a binding to C5aR1 and C5aR2 (C5L2) mediates the formation of neutrophil extracellular traps and release of cytotoxic histones to the extracellular space, which is believed to act as a pathogenetic process of acute respiratory distress syndrome (ARDS) [19] and promote tumor growth and metastasis. [20]

Related Research Articles

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<span class="mw-page-title-main">Granulocyte</span> Category of white blood cells

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They have varying shapes (morphology) of the nucleus ; and are referred to as polymorphonuclear leukocytes. In common terms, polymorphonuclear granulocyte refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have varying morphology. Granulocytes are produced via granulopoiesis in the bone marrow.

<span class="mw-page-title-main">Acute-phase protein</span> Class of proteins involved in inflammation

Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase or decrease in response to inflammation. This response is called the acute-phase reaction. The acute-phase reaction characteristically involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors. The terms acute-phase protein and acute-phase reactant (APR) are often used synonymously, although some APRs are polypeptides rather than proteins.

<span class="mw-page-title-main">Anaphylatoxin</span>

Anaphylatoxins, or complement peptides, are fragments that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense. They have a wide variety of biological activities and are proteolytically activated by cleavage at a specific site, forming a- and b-fragments. A-fragments form distinct structural domains of approximately 76 amino acids, coded for by a single exon within the complement protein gene. The C3a, C4a and C5a components are referred to as anaphylatoxins: they cause smooth muscle contraction, vasodilation, histamine release from mast cells, and enhanced vascular permeability. They also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals. The proteins are highly hydrophilic, with a mainly alpha-helical structure held together by 3 disulfide bridges.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">C3a receptor</span> Protein-coding gene in humans

The C3a receptor also known as complement component 3a receptor 1 (C3AR1) is a G protein-coupled receptor protein involved in the complement system.

<span class="mw-page-title-main">Neutrophil extracellular traps</span> Networks of fibres which bind pathogens

Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro activation with the pharmacological agent phorbol myristate acetate (PMA), Interleukin 8 (IL-8) or lipopolysaccharide (LPS), neutrophils release granule proteins and chromatin to form an extracellular fibril matrix known as NET through an active process.

<span class="mw-page-title-main">C5a receptor</span> Mammalian protein found in Homo sapiens

The C5a receptor also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a. It functions as a complement receptor. C5a receptor 1 modulates inflammatory responses, obesity, development and cancers. From a signaling transduction perspective, C5a receptor 1 activation is implicated in β-arrestin2 recruitment via Rab5a, coupling of Gαi proteins, ERK1/2 phosphorylation, calcium mobilization and Rho activation leading to downstream functions, such as secretion of cytokines, chemotaxis, and phagocytosis.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes and mast cells. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Leukocyte extravasation</span>

Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.

<span class="mw-page-title-main">C5AR2</span> Protein-coding gene in the species Homo sapiens

C5a anaphylatoxin chemotactic receptor 2 is a protein that in humans is encoded by the C5AR2 gene. It's a complement component G protein-coupled receptor, of class A (rhodopsin-like).

<span class="mw-page-title-main">GPR132</span> Protein-coding gene in the species Homo sapiens

G protein coupled receptor 132, also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e. GPR4, GPR68 (OGR1), and GPR65 (TDAG8), G2A is a G protein coupled receptor that resides in the cell surface membrane, senses changes in extracellular pH, and can alter cellular function as a consequence of these changes. Subsequently, G2A was suggested to be a receptor for lysophosphatidylcholine (LPC). However, the roles of G2A as a pH-sensor or LPC receptor are disputed. Rather, current studies suggest that it is a receptor for certain metabolites of the polyunsaturated fatty acid, linoleic acid.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">C3a (complement)</span>

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmin because they serve as a warning sign for the organism to alert it of any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern-recognition receptor. Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

References

  1. 1 2 3 Manthey HD, Woodruff TM, Taylor SM, Monk PN (November 2009). "Complement component 5a (C5a)". The International Journal of Biochemistry & Cell Biology. 41 (11): 2114–2117. doi:10.1016/j.biocel.2009.04.005. PMID   19464229.
  2. ↑ Klos A, Wende E, Wareham KJ, Monk PN (January 2013). "International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors". Pharmacological Reviews. 65 (1): 500–543. doi: 10.1124/pr.111.005223 . PMID   23383423.
  3. ↑ Ward PA (February 2004). "The dark side of C5a in sepsis". Nature Reviews. Immunology. 4 (2): 133–142. doi:10.1038/nri1269. PMID   15040586. S2CID   22630287.
  4. ↑ Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, et al. (April 2016). "Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists". Scientific Reports. 6 (1): 24575. doi:10.1038/srep24575. PMC   4837355 . PMID   27094554.
  5. ↑ Gerard NP, Gerard C (February 1991). "The chemotactic receptor for human C5a anaphylatoxin". Nature. 349 (6310): 614–617. doi:10.1038/349614a0. PMID   1847994. S2CID   4338594.
  6. ↑ Fujita T (14 October 1999). Boulay F (ed.). "PROW and IWHLDA present the GUIDE on: CD88". Protein Reviews on the Web. Archived from the original on 2008-07-24.
  7. ↑ Seow V, Lim J, Iyer A, Suen JY, Ariffin JK, Hohenhaus DM, et al. (October 2013). "Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a". Journal of Immunology. 191 (8): 4308–4316. doi: 10.4049/jimmunol.1301355 . PMID   24043889. S2CID   207429042.
  8. ↑ Raby AC, Holst B, Davies J, Colmont C, Laumonnier Y, Coles B, et al. (September 2011). "TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2". European Journal of Immunology. 41 (9): 2741–2752. doi:10.1002/eji.201041350. PMC   3638321 . PMID   21630250.
  9. ↑ Klos A, Wende E, Wareham KJ, Monk PN (January 2013). "International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors". Pharmacological Reviews. 65 (1): 500–543. doi: 10.1124/pr.111.005223 . PMID   23383423.
  10. ↑ Woodruff TM, Crane JW, Proctor LM, Buller KM, Shek AB, de Vos K, et al. (July 2006). "Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration". FASEB Journal. 20 (9): 1407–1417. doi:10.1096/fj.05-5814com. PMID   16816116. S2CID   9206660.
  11. ↑ Jain U, Woodruff TM, Stadnyk AW (January 2013). "The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10". British Journal of Pharmacology. 168 (2): 488–501. doi:10.1111/j.1476-5381.2012.02183.x. PMC   3572573 . PMID   22924972.
  12. ↑ Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF, et al. (September 2002). "Complement-induced impairment of innate immunity during sepsis". Journal of Immunology. 169 (6): 3223–3231. doi: 10.4049/jimmunol.169.6.3223 . PMID   12218141.
  13. ↑ Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, et al. (July 2009). "C5a mediates peripheral blood neutrophil dysfunction in critically ill patients". American Journal of Respiratory and Critical Care Medicine. 180 (1): 19–28. doi:10.1164/rccm.200812-1928OC. PMC   2948533 . PMID   19324972.
  14. ↑ Morris AC, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, et al. (May 2011). "C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients". Blood. 117 (19): 5178–5188. doi: 10.1182/blood-2010-08-304667 . PMID   21292772.
  15. ↑ Conway Morris A, Datta D, Shankar-Hari M, Stephen J, Weir CJ, Rennie J, et al. (May 2018). "Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study". Intensive Care Medicine. 44 (5): 627–635. doi:10.1007/s00134-018-5247-0. PMC   6006236 . PMID   29915941.
  16. ↑ Conway Morris A, Anderson N, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, et al. (November 2013). "Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients". British Journal of Anaesthesia. 111 (5): 778–787. doi: 10.1093/bja/aet205 . PMID   23756248.
  17. ↑ Unnewehr H, Rittirsch D, Sarma JV, Zetoune F, Flierl MA, Perl M, et al. (April 2013). "Changes and regulation of the C5a receptor on neutrophils during septic shock in humans". Journal of Immunology. 190 (8): 4215–4225. doi: 10.4049/jimmunol.1200534 . PMID   23479227.
  18. ↑ Wood AJ, Vassallo AM, Ruchaud-Sparagano MH, Scott J, Zinnato C, Gonzalez-Tejedo C, et al. (August 2020). "C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling". JCI Insight. 5 (15). doi: 10.1172/jci.insight.137029 . PMC   7455072 . PMID   32634128.
  19. ↑ Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, et al. (December 2013). "Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury". FASEB Journal. 27 (12): 5010–5021. doi: 10.1096/fj.13-236380 . PMC   3834784 . PMID   23982144.
  20. ↑ Ortiz-Espinosa S, Morales X, Senent Y, Alignani D, Tavira B, Macaya I, et al. (March 2022). "Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis". Cancer Letters. 529: 70–84. doi: 10.1016/j.canlet.2021.12.027 . PMID   34971753.
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