Title: Platelets Affect the Structure and Function of C-Reactive Protein
Abstract: HomeCirculation ResearchVol. 105, No. 2Platelets Affect the Structure and Function of C-Reactive Protein Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPlatelets Affect the Structure and Function of C-Reactive Protein János G. Filep János G. FilepJános G. Filep From the Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montréal, Québec, Canada. Originally published17 Jul 2009https://doi.org/10.1161/CIRCRESAHA.109.202010Circulation Research. 2009;105:109–111C-reactive protein (CRP) is an acute-phase reactant and an active regulator of the innate immune system.1,2 Prospective clinical studies have shown that elevations in baseline CRP levels confer, albeit to varying degrees, additional prognostic value for predicting future cardiovascular events and death across all levels of the Framingham risk score.3 CRP has been implicated in multiple aspects of atherogenesis and plaque vulnerability; however, a direct pathogenetic role for CRP in these events is presently controversial.4,5 CRP has at least 2 conformationally distinct forms, native pentameric (p)CRP and monomeric (m)CRP. Native CRP consists of 5 identical subunits arranged in a cyclic pentamer. Loss of pentameric symmetry in pCRP, yielding mCRP, is associated with expression of distinct bioactivities.6–9 To date, little is known about the in vivo source(s) of mCRP.Platelets represent an important interface between thrombosis, innate and adaptive immunity, and atherogenesis.10 Platelet-triggered inflammatory pathways contribute to atherosclerotic lesion formation and atherothrombosis.10 In this issue of Circulation Research, Eisenhardt et al11 provide new insights into the relationship of platelets, CRP, and inflammation. They show that activated platelets dissociate pCRP into mCRP and provide evidence, suggesting that mCRP, rather than pCRP, localizes monocyte-mediated inflammation to the atherosclerotic plaque.Native CRP is thought to be very stable and is not expected to dissociate into separate subunits without denaturation.12 However, calcium-dependent binding of pCRP to liposomes or cell membranes results in separation into subunits.13 Eisenhardt et al11 show that binding of pCRP to lysophosphatidylcholine expressed on the surface of activated platelets and apoptotic monocytic THP-1 cells triggers its rapid dissociation into mCRP. Formation of mCRP involves dissociation of the CRP pentameric disk, resulting in a structural change from predominantly β-sheet structure to an α-helical structure and expression of intersubunit contact residues, in particular residues 197 to 202, the predominant epitope only expressed on mCRP.14 mCRP-specific antigen has been detected in inflamed tissues.15Immunohistological staining of human atherosclerotic lesions consistently places CRP within the lesion, frequently along with the terminal complement complex.4,5 Because most anti-CRP antibodies, including the widely used antibody clone 8, recognize both pCRP and mCRP,16 it is uncertain whether lesions express mCRP, pCRP, or both. Eisenhardt et al11 show that human aortic and coronary artery atherosclerotic plaques stained with the clone 8 antibody and a specific anti-mCRP antibody but not with a specific anti-pCRP antibody, indicating accumulation of mCRP rather than pCRP in atherosclerotic lesions. mCRP-staining correlated with areas that stained for macrophages or platelets, suggesting generation of mCRP by these cells. Formal colocalization studies would lend additional support to this notion. Future studies are needed to investigate whether deposition of pCRP into lesions precedes in situ mCRP generation. Of note, CRP mRNA is also expressed (at very low levels) in blood vessel wall cells, although it is unlikely whether these cells are major sources for CRP in plaques.17Although pCRP and mCRP exhibit distinct biological activities (see the Figure), it is controversial which form mediates CRP's proinflammatory actions. For instance, pCRP induces proinflammatory cytokine release from endothelial cells and monocytes and evokes endothelial dysfunction and monocyte adhesion to the endothelium.4 Other studies found mCRP to be a considerably more potent activator of endothelial cells and monocytes than pCRP.6,11 pCRP and mCRP exert opposing actions on neutrophil trafficking into tissues8 and platelet deposition and thrombus growth.7,9 Transgenic expression of human CRP protects mice against endotoxin shock and microbial pathogens.2 Transgenic expression of CRP in apolipoprotein E–null mice has been reported to accelerate,16,18 to show no effect,19,20 or even to slow atherosclerosis development.21 Such divergent results are not easily explained and may reflect inherent difficulties in interpreting results from mouse models of atherogenesis.5Download figureDownload PowerPointFigure. Pro- and antiinflammatory actions of native pCRP and mCRP. Both pCRP and mCRP bind to endothelial cells, platelets, neutrophils, and monocytes via specific Fcγ receptors or lipid rafts. Several signaling mechanisms are simultaneously activated, including the activation of various kinases and transcription factors. mCRP possesses potent proinflammatory and prothrombotic actions, whereas pCRP mainly sustains an antiinflammatory innate immune response. In this issue of Circulation Research, activated platelets are identified as a switch to induce dissociation of pCRP into mCRP. Of note, pCRP through inhibition of insulin activation of endothelial nitric oxide synthase and activation of nuclear factor κB in monocytes may contribute to endothelial dysfunction and release of proinflammatory cytokines, respectively. ABCA1 indicates ATP-binding cassette transporter A1; EC, endothelial cell; ICAM, intercellular adhesion molecule; IL-8, interleukin-8; lr, lipid rafts; LXRα, liver X receptor α; PMN, polymorphonuclear leukocytes; ROS, reactive oxygen species.An unexpected observation was that mCRP-induced monocyte adhesion could be partially inhibited by blockade of CD64 (FcγRI), CD32 (FcγRIIA), or CD16 (FcγRIII). In phagocytes and endothelial cells, pCRP binds primarily to CD32 and to some extent to CD64,22,23 whereas mCRP binds to CD16.24 Eisenhardt et al11 show that disruption of lipid rafts fully inhibited monocyte activation by mCRP. Although intriguing, the data should be interpreted with caution. In monocytes, binding of pCRP to CD64 and CD32 was found to activate nuclear factor κB and the nuclear liver X receptor-α.25 Nuclear factor κB regulates transcription of proinflammatory cytokines. Liver X receptor-α increases expression of the ATP-binding cassette transporter A1 and suppresses genes involved in inflammatory signaling and apoptosis.25 It is tempting to speculate that an as yet unidentified molecular switch may direct proinflammatory versus antiinflammatory responses in monocytes. Furthermore, cell-specific differences in molecular mechanisms activated by pCRP and mCRP should also be considered. For instance, pCRP inhibits insulin activation of endothelial nitric oxide synthase via FcγRIIB and SHIP-1 (Src homology 2 domain-containing inositol 5`-phosphate),26 whereas mCRP induces cytokine release and upregulates expression of adhesion molecules on endothelial cells through CD16, lipid rafts microdomains, and p38 mitogen-activated protein kinase.4,27In conclusion, the article by Eisenhardt et al11 brings the concept of platelets being important in the formation of mCRP and thus localizing inflammation to atherosclerotic plaques a step closer to the clinical setting. These observations highlight that an analysis of CRP in the plasma alone may not be suitable to reflect its function and to serve as a biomarker in atherosclerosis. The benefits of therapeutically targeting CRP were recently shown in a rat model of myocardial infarction.28 Considering the pro- and antiinflammatory actions of CRP, it remains a future challenge to investigate whether therapeutic interventions aimed to selectively block its proinflammatory actions, perhaps by preventing dissociation of native CRP into mCRP, could have clinical benefits.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingSupported by Canadian Institutes of Health Research grants MOP-64283 and MOP-94851.DisclosuresNone.FootnotesCorrespondence to János G. Filep, MD, Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, 5415 boulevard de l'Assomption, Montréal, QC, Canada H1T 2M4. E-mail [email protected] References 1 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. 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Fay W (2010) Linking inflammation and thrombosis: Role of C-reactive protein, World Journal of Cardiology, 10.4330/wjc.v2.i11.365, 2:11, (365), . July 17, 2009Vol 105, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.109.202010PMID: 19608987 Originally publishedJuly 17, 2009 KeywordsmonocytesatherosclerosisinflammationC-reactive proteinplateletsPDF download Advertisement