Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques.
C-reactive protein (CRP) is a predictor of cardiovascular risk. It circulates as a pentamer (pentameric CRP) in plasma. The in vivo existence of monomeric (m)CRP has been postulated, but its function and source are not clear. We show that mCRP is deposited in human aortic and carotid atherosclerotic plaques but not in healthy vessels. pCRP is found neither in healthy nor in diseased vessels. As source of mCRP, we identify a mechanism of dissociation of pCRP to mCRP. We report that activated platelets, which play a central role in cardiovascular events, mediate this dissociation via lysophosphatidylcholine, which is present on activated but not resting platelets. Furthermore, the dissociation of pCRP to mCRP can also be mediated by apoptotic monocytic THP-1 and Jurkat T cells. The functional consequence is the unmasking of proinflammatory effects of CRP as demonstrated in experimental settings that are pathophysiologically relevant for atherogenesis: compared to pCRP, mCRP induces enhanced monocyte chemotaxis; monocyte activation, as determined by conformational change of integrin Mac-1; generation of reactive oxygen species; and monocyte adhesion under static and physiological flow conditions. In conclusion, we demonstrate mCRP generation via pCRP dissociation on activated platelets and H(2)O(2)-treated apoptotic THP-1 and Jurkat T cells, thereby identifying a mechanism of localized unmasking of the proinflammatory properties of CRP. This novel mechanism provides a potential link between the established cardiovascular risk marker, circulating pCRP, and localized platelet-mediated inflammatory and proatherogenic effects.
Eisenhardt
Steffen U
SU
University of Freiburg Medical Center, Department of Plastic and Hand Surgery, Hugstetter Strasse 55, 79106 Freiburg, Germany. steffen.eisenhardt@uniklinik-freiburg.de
Habersberger
Jonathon
J
Murphy
Andrew
A
Chen
Yung-Chih
YC
Woollard
Kevin J
KJ
Bassler
Nicole
N
Qian
Hongwei
H
von Zur Muhlen
Constantin
C
Hagemeyer
Christoph E
CE
Ahrens
Ingo
I
Chin-Dusting
Jaye
J
Bobik
Alex
A
Peter
Karlheinz
K
D001018:Aortic Diseases / Q000097:blood* / Q000276:immunology / Q000473:pathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000097:blood* / Q000276:immunology / Q000473:pathology; D001344:Autopsy; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D002097:C-Reactive Protein / Q000737:chemistry / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000097:blood* / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood* / Q000737:chemistry; D019169:Jurkat Cells; D008244:Lysophosphatidylcholines / Q000097:blood; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008563:Membrane Lipids / Q000097:blood; D021962:Membrane Microdomains / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D015539:Platelet Activation; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
D018836:Inflammation Mediators; D008244:Lysophosphatidylcholines; D016177:Macrophage-1 Antigen; D008563:Membrane Lipids; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D011994:Recombinant Proteins; D002097:C-Reactive Protein