Skip to main content

Advertisement

SpringerLink
Log in

Regulation of C-reactive protein conformation in inflammation

  • Review
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

C-reactive protein (CRP) is a non-specific diagnostic marker of inflammation and an evolutionarily conserved protein with roles in innate immune signaling. Natural CRP is composed of five identical globular subunits that form a pentamer, but the role of pentameric CRP (pCRP) during inflammatory pathogenesis remains controversial. Emerging evidence suggests that pCRP can be dissociated into monomeric CRP (mCRP) that has major roles in host defenses and inflammation. Here, we discuss our current knowledge of the dissociation mechanisms of pCRP and summarize the stepwise conformational transition model to mCRP to elucidate how CRP dissociation contributes to proinflammatory activity. These discussions will evoke new understanding of this ancient protein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Shrive AK, Gheetham GM, Holden D, Myles DA, Turnell WG, Volanakis JE, Pepys MB, Bloomer AC, Greenhough TJ. Three dimensional structure of human C-reactive protein. Nat Struct Mol Biol. 1996;3:346–54. https://doi.org/10.1038/nsb0496-346.

    Article  CAS  Google Scholar 

  2. Potempa LA, Maldonado BA, Laurent P, Zemel ES, Gewurz H. Antigenic, electrophoretic and binding alterations of human C-reactive protein modified selectively in the absence of calcium. Mol Immunol. 1983;20:1165–75. https://doi.org/10.1016/0161-5890(83)90140-2.

    Article  CAS  PubMed  Google Scholar 

  3. Potempa LA, Yao ZY, Ji SR, Filep JG, Wu Y. Solubilization and purification of recombinant modified C-reactive protein from inclusion bodies using reversible anhydride modification. Biophys Rep. 2015;1:18–33. https://doi.org/10.1007/s41048-015-0003-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. 1999;7:169–77.

    Article  CAS  Google Scholar 

  5. Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396:1181–97. https://doi.org/10.1515/hsz-2015-0149.

    Article  CAS  PubMed  Google Scholar 

  6. Kresl JJ, Potempa LA, Anderson BE. Conversion of native oligomeric to a modified monomeric form of human C-reactive protein. Int J Biochem Cell Biol. 1998;30:1415–26. https://doi.org/10.1016/S1357-2725(98)00078-8.

    Article  CAS  PubMed  Google Scholar 

  7. Ji SR, Wu Y, Zhu L, Potempa LA, Sheng FL, Lu W, Zhao J. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J. 2007;21:284–94. https://doi.org/10.1096/fj.06-6722com.

    Article  CAS  PubMed  Google Scholar 

  8. Ji SR, Wu Y, Potempa LA, Liang YH, Zhao J. Effect of modified C-reactive protein on complement activation: a possible complement regulatory role of modified or monomeric C-reactive protein in atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2006;26:935–41. https://doi.org/10.1161/01.atv.0000206211.21895.73.

    Article  CAS  PubMed  Google Scholar 

  9. Ji SR, Ma L, Bai CJ, Shi JM, Li HY, Potempa LA, Filep JG, Zhao J, Wu Y. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB J. 2009;23:1806–16. https://doi.org/10.1096/fj.08-116962.

    Article  CAS  PubMed  Google Scholar 

  10. Wang MY, Ji SR, Bai CJ, El Kebir D, Li HY, Shi JM, Zhu W, Costantino S, Zhou HH, Potempa LA, Zhao J, Filep JG, Wu Y. A redox switch in C-reactive protein modulates activation of endothelial cells. FASEB J. 2011;25:3186–96. https://doi.org/10.1096/fj.11-182741.

    Article  CAS  PubMed  Google Scholar 

  11. Braig D, Nero TL, Koch HG, Kaiser B, Wang X, Thiele JR, Morton CJ, Zeller J, Kiefer J, Potempa LA, Mellett NA, Miles LA, Du XJ, Meikle PJ, Huber-Lang M, Stark GB, Parker MW, Peter K, Eisenhardt SU. Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nat Commun. 2017;8:14188. https://doi.org/10.1038/ncomms14188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thiele JR, Habersberger J, Braig D, Schmidt Y, Goerendt K, Maurer V, Bannasch H, Scheichl A, Woollard KJ, von Dobschütz E. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation. 2014;130:35–50. https://doi.org/10.1161/CIRCULATIONAHA.113.007124.

    Article  CAS  PubMed  Google Scholar 

  13. Eisenhardt SU, Habersberger J, Murphy A, Chen YC, Woollard KJ, Bassler N, Qian H, von Zur Muhlen C, Hagemeyer CE, Ahrens I, Chin-Dusting J, Bobik A, Peter K. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res. 2009;105:128–37. https://doi.org/10.1161/CIRCRESAHA.108.190611.

    Article  CAS  PubMed  Google Scholar 

  14. Schwedler SB. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant. 2003;18:2300–7. https://doi.org/10.1093/ndt/gfg407.

    Article  CAS  PubMed  Google Scholar 

  15. Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU. Targeting C-reactive protein in inflammatory disease by preventing conformational changes. Mediat Inflamm. 2015;2015:372432. https://doi.org/10.1155/2015/372432.

    Article  CAS  Google Scholar 

  16. Li QY, Li HY, Fu G, Yu F, Wu Y, Zhao MH. Autoantibodies against C-reactive protein influence complement activation and clinical course in lupus nephritis. J Am Soc Nephrol. 2017;28:3044–54. https://doi.org/10.1681/ASN.2016070735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Crawford JR, Trial J, Nambi V, Hoogeveen RC, Taffet GE, Entman ML. Plasma levels of endothelial microparticles bearing monomeric C-reactive protein are increased in peripheral artery disease. J Cardiovasc Transl Res. 2016;9:184–93. https://doi.org/10.1007/s12265-016-9678-0.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang L, Li HY, Li W, Shen ZY, Wang YD, Ji SR, Wu Y. An ELISA assay for quantifying monomeric C-reactive protein in plasma. Front Immunol. 2018;9:511. https://doi.org/10.3389/fimmu.2018.00511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mihlan M, Stippa S, Jozsi M, Zipfel PF. Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H. Cell Death Differ. 2009;16:1630–40. https://doi.org/10.1038/cdd.2009.103.

    Article  CAS  PubMed  Google Scholar 

  20. O’Flynn J, van der Pol P, Dixon KO, Prohaszka Z, Daha MR, van Kooten C. Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin. Am J Physiol Renal Physiol. 2016;310:F1308–16. https://doi.org/10.1152/ajprenal.00645.2014.

    Article  CAS  PubMed  Google Scholar 

  21. Khreiss T, József L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation. 2004;109:2016–22.

    Article  CAS  PubMed  Google Scholar 

  22. Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106:1439–41. https://doi.org/10.1161/01.CIR.0000033116.22237.F9.

    Article  CAS  PubMed  Google Scholar 

  23. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165–8. https://doi.org/10.1161/01.CIR.102.18.2165.

    Article  CAS  PubMed  Google Scholar 

  24. Thiele JR, Habersberger J, Braig D, Schmidt Y, Goerendt K, Maurer V, Bannasch H, Scheichl A, Woollard KJ, von Dobschutz E, Kolodgie F, Virmani R, Stark GB, Peter K, Eisenhardt SU. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation. 2014;130:35–50. https://doi.org/10.1161/CIRCULATIONAHA.113.007124.

    Article  CAS  PubMed  Google Scholar 

  25. Potempa LA, Siegel JN, Fedel BA, Potempa RT, Gewurz H. Expression, detection and assay of a neoantigen (Neo-CRP) associated with a free, human C-reactive protein subunit. Mol Immunol. 1987;24:531–41. https://doi.org/10.1016/0161-5890(87)90028-9.

    Article  CAS  PubMed  Google Scholar 

  26. Wang MS, Messersmith RE, Reed SM. Membrane curvature recognition by C-reactive protein using lipoprotein mimics. Soft Matter. 2012;8:7909–18. https://doi.org/10.1039/C2SM25779C.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Poon IKH, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14:166–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Habersberger J, Strang F, Scheichl A, Htun N, Bassler N, Merivirta RM, Diehl P, Krippner G, Meikle P, Eisenhardt SU, Meredith I, Peter K. Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction. Cardiovasc Res. 2012;96:64–72. https://doi.org/10.1093/cvr/cvs237.

    Article  CAS  PubMed  Google Scholar 

  29. Strang F, Scheichl A, Chen YC, Wang X, Htun NM, Bassler N, Eisenhardt SU, Habersberger J, Peter K. Amyloid plaques dissociate pentameric to monomeric C-reactive protein: a novel pathomechanism driving cortical inflammation in Alzheimer’s disease? Brain Pathol. 2012;22:337–46. https://doi.org/10.1111/j.1750-3639.2011.00539.x.

    Article  CAS  PubMed  Google Scholar 

  30. Khreiss T, József L, Hossain S, Chan JS, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem. 2002;277:40775–81. https://doi.org/10.1074/jbc.M205378200.

    Article  CAS  PubMed  Google Scholar 

  31. Zouki C, Haas B, Chan JS, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion. J Immunol. 2001;167:5355–61. https://doi.org/10.4049/jimmunol.167.9.5355.

    Article  CAS  PubMed  Google Scholar 

  32. Heuertz RM, Schneider GP, Potempa LA, Webster RO. Native and modified C-reactive protein bind different receptors on human neutrophils. Int J Biochem Cell Biol. 2005;37:320–35. https://doi.org/10.1016/j.biocel.2004.07.002.

    Article  CAS  PubMed  Google Scholar 

  33. Khreiss T, Jozsef L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation. 2004;109:2016–22. https://doi.org/10.1161/01.CIR.0000125527.41598.68.

    Article  CAS  PubMed  Google Scholar 

  34. Khreiss T, József L, Potempa LA, Filep JG. Opposing effects of C-reactive protein isoforms on shear-induced neutrophil-platelet adhesion and neutrophil aggregation in whole blood. Circulation. 2004;110:2713–20. https://doi.org/10.1161/01.CIR.0000146846.00816.DD.

    Article  CAS  PubMed  Google Scholar 

  35. Li HY, Wang J, Meng F, Jia ZK, Su Y, Bai QF, Lv LL, Ma FR, Potempa LA, Yan YB, Ji SR, Wu Y. An intrinsically disordered motif mediates diverse actions of monomeric C-reactive protein. J Biol Chem. 2016;291:8795–804. https://doi.org/10.1074/jbc.M115.695023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kinoshita CM, Ying SC, Hugli TE, Siegel JN, Potempa LA, Jiang H, Houghten RA, Gewurz H. Elucidation of a protease-sensitive site involved in the binding of calcium to C-reactive protein. Biochemistry. 1989;28:9840–8.

    Article  CAS  PubMed  Google Scholar 

  37. Ying SC, Shephard E, De Beer FC, Siegel JN, Harris D, Gewurz BE, Fridkin M, Gewurz H. Localization of sequence-determined neoepitopes and neutrophil digestion fragments of C-reactive protein utilizing monoclonal antibodies and synthetic peptides. Mol Immunol. 1992;29:677–87.

    Article  CAS  PubMed  Google Scholar 

  38. Shephard EG, Beer SM, Anderson R, Strachan AF, Nel AE, de Beer FC. Generation of biologically active C-reactive protein peptides by a neutral protease on the membrane of phorbol myristate acetate-stimulated neutrophils. J Immunol. 1989;143:2974–81.

    CAS  PubMed  Google Scholar 

  39. Shephard EG, Anderson R, Rosen O, Myer, Fridkin M, Strachan AF, De Beer FC. Peptides generated from C-reactive protein by a neutrophil membrane protease. Amino acid sequence and effects of peptides on neutrophil oxidative metabolism and chemotaxis. J Immunol. 1990;145:1469–76.

    CAS  PubMed  Google Scholar 

  40. Heuertz RM, Ahmed N, Webster RO. Peptides derived from C-reactive protein inhibit neutrophil alveolitis. J Immunol. 1996;156:3412–7.

    CAS  PubMed  Google Scholar 

  41. El Kebir D, Zhang Y, Potempa LA, Wu Y, Fournier A, Filep JG. C-reactive protein-derived peptide 201-206 inhibits neutrophil adhesion to endothelial cells and platelets through CD32. J Leukoc Biol. 2011;90:1167–75. https://doi.org/10.1189/jlb.0111032.

    Article  CAS  PubMed  Google Scholar 

  42. Ji SR, Wu Y, Potempa LA, Qiu Q, Zhao J. Interactions of C-reactive protein with low-density lipoproteins: implications for an active role of modified C-reactive protein in atherosclerosis. Int J Biochem Cell Biol. 2006;38:648–61. https://doi.org/10.1016/j.biocel.2005.11.004.

    Article  CAS  PubMed  Google Scholar 

  43. Caprio V, Badimon L, Di Napoli M, Fang WH, Ferris GR, Guo B, Iemma RS, Liu D, Zeinolabediny Y, Slevin M. pCRP-mCRP dissociation mechanisms as potential targets for the development of small-molecule anti-inflammatory chemotherapeutics. Front Immunol. 2018;9:1089. https://doi.org/10.3389/fimmu.2018.01089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li HY, Liu XL, Liu YT, Jia ZK, Filep JG, Potempa LA, Ji SR, Wu Y. Matrix sieving-enforced retrograde transcytosis regulates tissue accumulation of C-reactive protein. Cardiovasc Res. 2019;115:440–52. https://doi.org/10.1093/cvr/cvy181.

    Article  CAS  PubMed  Google Scholar 

  45. Jabs WJ, Lögering BA, Gerke P, Kreft B, Wolber EM, Klinger MHF, Fricke L, Steinhoff J. The kidney as a second site of human C-reactive protein formation in vivo. Eur J Immunol. 2003;33:152–61.

    Article  CAS  PubMed  Google Scholar 

  46. Ramage L, Proudfoot L, Guy K. Expression of C-reactive protein in human lung epithelial cells and upregulation by cytokines and carbon particles. Inhal Toxicol. 2004;16:607–13. https://doi.org/10.1080/08958370490464599.

    Article  CAS  PubMed  Google Scholar 

  47. Yasojima K, Schwab C, McGeer EG, McGeer PL. Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease. Brain Res. 2000;887:80–9. https://doi.org/10.1016/s0006-8993(00)02970-x.

    Article  CAS  PubMed  Google Scholar 

  48. Calabro P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol. 2005;46:1112–3. https://doi.org/10.1016/j.jacc.2005.06.017.

    Article  CAS  PubMed  Google Scholar 

  49. Kuta AE, Baum LL. C-reactive protein is produced by a small number of normal human peripheral blood lymphocytes. J Exp Med. 1986;164:321–6. https://doi.org/10.1084/jem.164.1.321.

    Article  CAS  PubMed  Google Scholar 

  50. Bello-Perez M, Falco A, Medina R, Encinar JA, Novoa B, Perez L, Estepa A, Coll J. Structure and functionalities of the human C-reactive protein compared to the zebrafish multigene family of C-reactive-like proteins. Dev Comp Immunol. 2016. https://doi.org/10.1016/j.dci.2016.12.001.

    Article  PubMed  Google Scholar 

  51. Chen R, Qi J, Yuan H, Wu Y, Hu W, Xia C. Crystal structures for short-chain pentraxin from zebrafish demonstrate a cyclic trimer with new recognition and effector faces. J Struct Biol. 2015;189:259–68. https://doi.org/10.1016/j.jsb.2015.01.001.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang L, Liu SH, Wright TT, Shen ZY, Li HY, Zhu W, Potempa LA, Ji SR, Szalai AJ, Wu Y. C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. J Immunol. 2015;194:5243–52. https://doi.org/10.4049/jimmunol.1402909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440:1217–21. https://doi.org/10.1038/nature04672.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose articles have not been cited due to space limitations. This article was supported by Research Project of Xi’an Post-doctoral Innovative Base to Z. Yao, and Major Project of Xi’an Children’s Hospital (Grant No. 2018A05 to Z. Yao).

Author information

Authors and Affiliations

  1. Children’s Research Institute, Xi’an Key Laboratory of Children’s Health and Diseases, Affiliated Children Hospital, Xi’an Jiaotong University, 69# Xijuyuan Lane, Lianhu District, Xi’an, 710003, Shaanxi, China

    ZhenYu Yao, Yanmin Zhang & HaiBin Wu

Authors
  1. ZhenYu Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanmin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. HaiBin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to HaiBin Wu.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yao, Z., Zhang, Y. & Wu, H. Regulation of C-reactive protein conformation in inflammation. Inflamm. Res. 68, 815–823 (2019). https://doi.org/10.1007/s00011-019-01269-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-019-01269-1

Keywords

Search

Navigation