anaphylatoxin c5a receptor

Summary

Summary: A G-protein-coupled receptor that signals an increase in intracellular calcium in response to the potent ANAPHYLATOXIN peptide COMPLEMENT C5A.

Top Publications

  1. Ji H, Ohmura K, Mahmood U, Lee D, Hofhuis F, Boackle S, et al. Arthritis critically dependent on innate immune system players. Immunity. 2002;16:157-68 pubmed
    ..We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response. ..
  2. Gerard C, Gerard N. C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol. 1994;12:775-808 pubmed
    ..Where appropriate, relevant work on related seven transmembrane segment receptors is discussed. ..
  3. Monk P, Scola A, Madala P, Fairlie D. Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol. 2007;152:429-48 pubmed
    ..This review will highlight major developments in C5a receptor research that support C5aR as an important therapeutic target. The intriguing possibilities raised by the existence of a non-signalling C5a receptor are also discussed. ..
  4. Köhl J. Drug evaluation: the C5a receptor antagonist PMX-53. Curr Opin Mol Ther. 2006;8:529-38 pubmed
    ..Peptech is developing PMX-53, a complement C5a inhibitor for the potential treatment of inflammatory disorders, including rheumatoid arthritis and psoriasis. Phase Ib/IIa clinical trials have been completed for both indications. ..
  5. Köhl J, Wills Karp M. Complement regulates inhalation tolerance at the dendritic cell/T cell interface. Mol Immunol. 2007;44:44-56 pubmed
    ..In this context, an unexpected role for the anaphylatoxin C5a receptor in allergic sensitization has been found...
  6. Mollnes T, Brekke O, Fung M, Fure H, Christiansen D, Bergseth G, et al. Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood. 2002;100:1869-77 pubmed
    ..Complement inhibition may have therapeutic implications in oxidative burst-induced tissue damage. ..
  7. Rittirsch D, Flierl M, Nadeau B, Day D, Huber Lang M, Mackay C, et al. Functional roles for C5a receptors in sepsis. Nat Med. 2008;14:551-7 pubmed publisher
    ..Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor. ..
  8. Mullaly S, Kubes P. Mast cell-expressed complement receptor, not TLR2, is the main detector of zymosan in peritonitis. Eur J Immunol. 2007;37:224-34 pubmed
  9. Riedemann N, Neff T, Guo R, Bernacki K, Laudes I, Sarma J, et al. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol. 2003;170:503-7 pubmed

More Information

Publications62

  1. Crass T, Ames R, Sarau H, Tornetta M, Foley J, Kohl J, et al. Chimeric receptors of the human C3a receptor and C5a receptor (CD88). J Biol Chem. 1999;274:8367-70 pubmed
    ..Replacement of the C3aR N terminus by the C5aR sequence, however, lead to the generation of a true hybrid C3a/C5a receptor, which bound and functionally responded to both ligands, C3a and C5a. ..
  2. Huber Lang M, Younkin E, Sarma J, McGuire S, Lu K, Guo R, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol. 2002;169:3223-31 pubmed
    ..These data identify a molecular basis for defective innate immunity involving neutrophils during sepsis. ..
  3. Gerard N, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. Nature. 1991;349:614-7 pubmed
    ..The deduced amino-acid sequence of the receptor reveals the expected motifs befitting its interaction with cellular GTP-binding proteins. ..
  4. Riedemann N, Guo R, Sarma V, Laudes I, Huber Lang M, Warner R, et al. Expression and function of the C5a receptor in rat alveolar epithelial cells. J Immunol. 2002;168:1919-25 pubmed
    ..The functional outcome is enhanced release of proinflammatory mediators. These data underscore the phlogistic potential of RAEC and the ability of C5a to enhance the phlogistic responses of RAEC. ..
  5. Schraufstatter I, Trieu K, Sikora L, Sriramarao P, DiScipio R. Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol. 2002;169:2102-10 pubmed
    ..The C5aR in endothelial cells thus uses a signaling cascade-transactivation of the EGFR-that does not exist in leukocytes, while the C3aR couples to a different G protein, presumably G(alpha12/13). ..
  6. Peng T, Hao L, Madri J, Su X, Elias J, Stahl G, et al. Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response. J Clin Invest. 2005;115:1590-600 pubmed
    ..This study suggests that targeting C5 is a potential clinical approach for treating patients with asthma. ..
  7. Niederbichler A, Hoesel L, Westfall M, Gao H, Ipaktchi K, Sun L, et al. An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med. 2006;203:53-61 pubmed
    ..These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a-C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance. ..
  8. Riedemann N, Guo R, Laudes I, Keller K, Sarma V, Padgaonkar V, et al. C5a receptor and thymocyte apoptosis in sepsis. FASEB J. 2002;16:887-8 pubmed
    ..These data provide the first direct evidence that in the early onset of sepsis, increased expression of C5aR occurs in thymocytes, which increases their susceptibility to C5a-induced apoptosis. ..
  9. Fonseca M, Ager R, Chu S, Yazan O, Sanderson S, LaFerla F, et al. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol. 2009;183:1375-83 pubmed publisher
    ..e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients. ..
  10. Foreman K, Vaporciyan A, Bonish B, Jones M, Johnson K, Glovsky M, et al. C5a-induced expression of P-selectin in endothelial cells. J Clin Invest. 1994;94:1147-55 pubmed
    ..These data suggest that C5a may be an important inflammatory mediator for the early adhesive interactions between neutrophils and endothelial cells in the acute inflammatory response. ..
  11. Fukuoka Y, Ember J, Hugli T. Cloning and characterization of rat C3a receptor: differential expression of rat C3a and C5a receptors by LPS stimulation. Biochem Biophys Res Commun. 1998;242:663-8 pubmed
    ..These results suggest that expression of C3aR and C5aR is independently regulated in rat cells and tissues. ..
  12. Stahel P, Kariya K, Shohami E, Barnum S, Eugster H, Trentz O, et al. Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. J Neuroimmunol. 2000;109:164-72 pubmed
    ..These data show that the posttraumatic neuronal expression of the C5aR is, at least in part, regulated by TNF and lymphotoxin-alpha at 7 days after trauma...
  13. Riedemann N, Guo R, Neff T, Laudes I, Keller K, Sarma V, et al. Increased C5a receptor expression in sepsis. J Clin Invest. 2002;110:101-8 pubmed
    ..These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis. ..
  14. Chen Z, Zhang X, Gonnella N, Pellas T, Boyar W, Ni F. Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin. J Biol Chem. 1998;273:10411-9 pubmed
    ..These results indicate that a short peptide sequence, or residues 21-30, of the C5a receptor N terminus may constitute the binding domain for the recognition site on C5a. ..
  15. Oskeritzian C, Zhao W, Min H, Xia H, Pozez A, Kiev J, et al. Surface CD88 functionally distinguishes the MCTC from the MCT type of human lung mast cell. J Allergy Clin Immunol. 2005;115:1162-8 pubmed
    ..MC(T) and MC(TC) types of human mast cells (MCs) are distinguished from one another on the basis of the protease compositions of their secretory granules, but their functional and developmental relationships have been uncertain...
  16. Köhl J, Baelder R, Lewkowich I, Pandey M, Hawlisch H, Wang L, et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J Clin Invest. 2006;116:783-96 pubmed
    ..e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment. ..
  17. Stahel P, Frei K, Eugster H, Fontana A, Hummel K, Wetsel R, et al. TNF-alpha-mediated expression of the receptor for anaphylatoxin C5a on neurons in experimental Listeria meningoencephalitis. J Immunol. 1997;159:861-9 pubmed
  18. Nilsson G, Johnell M, Hammer C, Tiffany H, Nilsson K, Metcalfe D, et al. C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway. J Immunol. 1996;157:1693-8 pubmed
    ..Direct chemoattraction of mast cells by C3a and C5a may help explain the rapid accumulation of mast cells at sites of inflammation. ..
  19. Schieferdecker H, Schlaf G, Koleva M, Gotze O, Jungermann K. Induction of functional anaphylatoxin C5a receptors on hepatocytes by in vivo treatment of rats with IL-6. J Immunol. 2000;164:5453-8 pubmed
  20. Strey C, Markiewski M, Mastellos D, Tudoran R, Spruce L, Greenbaum L, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198:913-23 pubmed
    ..These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration. ..
  21. Baumann U, Chouchakova N, Gewecke B, Kohl J, Carroll M, Schmidt R, et al. Distinct tissue site-specific requirements of mast cells and complement components C3/C5a receptor in IgG immune complex-induced injury of skin and lung. J Immunol. 2001;167:1022-7 pubmed
    ..Together, the phenotypes of C3(-/-) mice and Kit(W)/Kit(W-v) mice suggest that complement and mast cells have distinct tissue site-specific requirements acting by apparently distinct mechanisms in the initiation of IC inflammation...
  22. Ward P. The dark side of C5a in sepsis. Nat Rev Immunol. 2004;4:133-42 pubmed
    ..This review describes our present understanding of how and why sepsis is a life-threatening condition and how it might be more effectively treated. ..
  23. Laudes I, Chu J, Huber Lang M, Guo R, Riedemann N, Sarma J, et al. Expression and function of C5a receptor in mouse microvascular endothelial cells. J Immunol. 2002;169:5962-70 pubmed
  24. Soruri A, Kiafard Z, Dettmer C, Riggert J, Köhl J, Zwirner J. IL-4 down-regulates anaphylatoxin receptors in monocytes and dendritic cells and impairs anaphylatoxin-induced migration in vivo. J Immunol. 2003;170:3306-14 pubmed
    ..p. injected C5a. Overall, these data suggest that inhibition of a rapid anaphylatoxin-induced mobilization of monocytes and DC to inflamed tissues represents an important anti-inflammatory activity of the Th2 cytokine IL-4. ..
  25. Guo R, Ward P. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005;23:821-52 pubmed
    ..Herein, we review human and animal data describing the cellular and molecular mechanisms of C5a in the development of inflammatory disorders, sepsis, acute lung injury, ischemia-reperfusion injury, and asthma. ..
  26. Rahpeymai Y, Hietala M, Wilhelmsson U, Fotheringham A, Davies I, Nilsson A, et al. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 2006;25:1364-74 pubmed
    ..Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis. ..
  27. Farkas I, Takahashi M, Fukuda A, Yamamoto N, Akatsu H, Baranyi L, et al. Complement C5a receptor-mediated signaling may be involved in neurodegeneration in Alzheimer's disease. J Immunol. 2003;170:5764-71 pubmed
    ..Although staining was also positive in the vascular dementia brain, it disappeared in the brain with Alzheimer's disease. These results provide further support that C5aR may be involved in neurodegeneration. ..
  28. Floreani A, Wyatt T, Stoner J, Sanderson S, Thompson E, Allen Gipson D, et al. Smoke and C5a induce airway epithelial intercellular adhesion molecule-1 and cell adhesion. Am J Respir Cell Mol Biol. 2003;29:472-82 pubmed
    ..Our results may help explain the initiation and propagation of inflammatory events in vivo induced by chronic airway exposure to cigarette smoke. ..
  29. Zhang X, Lewkowich I, Köhl G, Clark J, Wills Karp M, Köhl J. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol. 2009;182:5123-30 pubmed publisher
    ..Ex vivo targeting of B7-H1 and B7-DC increased Th2 cytokine production from T cells of wild-type but not of C5aR-targeted mice, suggesting a protective role for C5a through regulation of B7 molecule expression on plasmacytoid DCs. ..
  30. Füreder W, Agis H, Willheim M, Bankl H, Maier U, Kishi K, et al. Differential expression of complement receptors on human basophils and mast cells. Evidence for mast cell heterogeneity and CD88/C5aR expression on skin mast cells. J Immunol. 1995;155:3152-60 pubmed
  31. Kim A, Dimitriou I, Holland M, Mastellos D, Mueller Y, Altman J, et al. Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses. J Immunol. 2004;173:2524-9 pubmed
    ..These results demonstrate that the binding of the C5a component of complement to the C5a receptor plays an important role in CD8(+) T cell responses. ..
  32. Crane J, Buller K. Systemic blockade of complement C5a receptors reduces lipopolysacharride-induced responses in the paraventricular nucleus and the central amygdala. Neurosci Lett. 2007;424:10-5 pubmed
    ..Our findings demonstrate that C5a may have a role in the activation of the HPA axis in response to systemic LPS. ..
  33. Farkas I, Varju P, Szabo E, Hrabovszky E, Okada N, Okada H, et al. Estrogen enhances expression of the complement C5a receptor and the C5a-agonist evoked calcium influx in hormone secreting neurons of the hypothalamus. Neurochem Int. 2008;52:846-56 pubmed
    ..Our results may serve a better understanding of the inflammatory and neurodegeneratory diseases of the hypothalamus and the related neuroendocrine and autonomic compensatory responses. ..
  34. Guo R, Riedemann N, Ward P. Role of C5a-C5aR interaction in sepsis. Shock. 2004;21:1-7 pubmed
    ..These data suggest that in sepsis C5a-C5aR signaling is excessive, resulting in paralysis of neutrophil function. Interception of either C5a or C5aR dramatically improves survival during experimental sepsis. ..
  35. Werfel T, Zwirner J, Oppermann M, Sieber A, Begemann G, Drommer W, et al. CD88 antibodies specifically bind to C5aR on dermal CD117+ and CD14+ cells and react with a desmosomal antigen in human skin. J Immunol. 1996;157:1729-35 pubmed
    ..Results with epithelial cells should be considered with caution, as the binding of CD88 mAb that were raised to a synthetic peptide sequence may be due to a cross-reactivity. ..
  36. Godau J, Heller T, Hawlisch H, Trappe M, Howells E, Best J, et al. C5a initiates the inflammatory cascade in immune complex peritonitis. J Immunol. 2004;173:3437-45 pubmed
    ..We conclude that complement activation and C5a generation are prerequisites for IC-induced inflammation through activating FcgammaR, which amplifies complement-induced inflammation in autoimmunity...
  37. Mastellos D, Papadimitriou J, Franchini S, Tsonis P, Lambris J. A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol. 2001;166:2479-86 pubmed
    ..These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis. ..
  38. Soruri A, Kim S, Kiafard Z, Zwirner J. Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody. Immunol Lett. 2003;88:47-52 pubmed
    ..Taken together, our results suggest that in the mouse expression of C5aR protein may be restricted to leukocytes of myeloid origin whereas previous evidence for C5aR expression on lymphoid cells may be reevaluated. ..
  39. O Barr S, Caguioa J, Gruol D, Perkins G, Ember J, Hugli T, et al. Neuronal expression of a functional receptor for the C5a complement activation fragment. J Immunol. 2001;166:4154-62 pubmed
    ..These results have implications for understanding the role of neuronal C5aR receptors in normal neuronal development, neuronal homeostasis, and neuroinflammatory conditions such as Alzheimer's disease. ..
  40. Haas P, van Strijp J. Anaphylatoxins: their role in bacterial infection and inflammation. Immunol Res. 2007;37:161-75 pubmed
  41. Humbles A, Lu B, Nilsson C, Lilly C, Israel E, Fujiwara Y, et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature. 2000;406:998-1001 pubmed
    ..We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma. ..
  42. Huber Lang M, Riedeman N, Sarma J, Younkin E, McGuire S, Laudes I, et al. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J. 2002;16:1567-74 pubmed
    ..These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a-induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP. ..
  43. Strachan A, Woodruff T, Haaima G, Fairlie D, Taylor S. A new small molecule C5a receptor antagonist inhibits the reverse-passive Arthus reaction and endotoxic shock in rats. J Immunol. 2000;164:6560-5 pubmed
    ..The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease...
  44. Shushakova N, Tkachuk N, Dangers M, Tkachuk S, Park J, Zwirner J, et al. Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor. J Cell Sci. 2005;118:2743-53 pubmed
    ..uPA) induces, via its specific receptor (uPAR, CD87), upregulated expression of the complement anaphylatoxin C5a receptor (C5aR, CD88), and modulates C5a-dependent functional responses...
  45. Woodruff T, Costantini K, Crane J, Atkin J, Monk P, Taylor S, et al. The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol. 2008;181:8727-34 pubmed
    ..This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease. ..
  46. Benard M, Gonzalez B, Schouft M, Falluel Morel A, Vaudry D, Chan P, et al. Characterization of C3a and C5a receptors in rat cerebellar granule neurons during maturation. Neuroprotective effect of C5a against apoptotic cell death. J Biol Chem. 2004;279:43487-96 pubmed
    ..Our results provide the first evidence that C3aR and C5aR are both expressed in cerebellar granule cells during development and that C5a, but not C3a, is a potent inhibitor of apoptotic cell death in cultured granule neurons. ..
  47. Riedemann N, Guo R, Hollmann T, Gao H, Neff T, Reuben J, et al. Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J. 2004;18:370-2 pubmed
    ..Accordingly, we suggest that induction of IL-6 after CLP is neutrophil and C5a/C5aR dependent, likely due to the ability of C5a to cause activation of ERK1/2 and p38 MAPK signaling pathways. ..
  48. Oppermann M, Gotze O. Plasma clearance of the human C5a anaphylatoxin by binding to leucocyte C5a receptors. Immunology. 1994;82:516-21 pubmed
    ..The binding of the C5a anaphylatoxin to cellular receptors represents an effective control mechanism that protects the organism from systemic effects of this potent phlogistic mediator. ..
  49. Gavrilyuk V, Kalinin S, Hilbush B, Middlecamp A, McGuire S, Pelligrino D, et al. Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. J Neurochem. 2005;92:1140-9 pubmed
    ..Changes in DST11 levels in diseased brain could therefore contribute to the progression of inflammatory damage. ..
  50. Bozic C, Lu B, Höpken U, Gerard C, Gerard N. Neurogenic amplification of immune complex inflammation. Science. 1996;273:1722-5 pubmed
    ..Immunoreactive substance P was measurable in fluids lining the lung at time points before neutrophil influx and may thus be involved in an early step in the inflammatory response to immune complexes in the lung...
  51. Guo R, Riedemann N, Bernacki K, Sarma V, Laudes I, Reuben J, et al. Neutrophil C5a receptor and the outcome in a rat model of sepsis. FASEB J. 2003;17:1889-91 pubmed
    ..These data suggest that neutrophil C5aR content represents an essential component of an efficient defense system in sepsis and may serve as a prognostic marker for the outcome. ..
  52. Maurya M, Subramaniam S. A kinetic model for calcium dynamics in RAW 264.7 cells: 2. Knockdown response and long-term response. Biophys J. 2007;93:729-40 pubmed
    ..Sensitivity analysis of long-term response shows that the mechanisms and parameters in the receptor recycle path are important for long-term calcium dynamics. ..
  53. Hori K, Hirashima M, Ueno M, Matsuda M, Waga S, Tsurufuji S, et al. Regulation of eosinophil migration by adult T cell leukemia-derived factor. J Immunol. 1993;151:5624-30 pubmed
    ..These results indicate a possible involvement of ADF in the recruitment of eosinophils through redox regulation by a dithiol reductase activity. ..