C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids

Abstract

C-reactive protein (CRP) is an acute-phase protein that binds specifically to phosphorylcholine (PC) as a component of microbial capsular polysaccharide and participates in the innate immune response against microorganisms. CRP elevation also is a major risk factor for cardiovascular disease. We previously demonstrated that EO6, an antioxidized LDL autoantibody, was a T15 clono-specific anti-PC antibody and specifically binds to PC on oxidized phosphatidylcholine (PtC) but not on native PtC. Similarly, EO6 binds apoptotic cells but not viable cells. In addition, such oxidized phospholipids are recognized by macrophage scavenger receptors, implying that these innate immune responses participate in the clearance because of their proinflammatory properties. We now report that CRP binds to oxidized LDL (OxLDL) and oxidized PtC (OxPtC), but does not bind to native, nonoxidized LDL nor to nonoxidized PtC, and its binding is mediated through the recognition of a PC moiety. Reciprocally, CRP binds to PC, which can be competed for by OxLDL and OxPtC but not by native LDL, nonoxidized PtC, or by oxidized phospholipids without the PC headgroup. CRP also binds to apoptotic cells, and this binding is competed for by OxLDL, OxPtC, and PC. These data suggest that CRP binds OxLDL and apoptotic cells by recognition of a PC moiety that becomes accessible as a result of oxidation of PtC molecule. We propose that, analogous to EO6 and scavenger receptors, CRP is a part of the innate immune response to oxidized PC-bearing phospholipids within OxLDL and on the plasma membranes of apoptotic cells.atherosclerosis ͉ innate immunity ͉ scavenger receptors ͉ autoantibody EO6

Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H

“…33 In addition, in atherosclerotic lesions, mCRP colocalizes with complement proteins C3b, iC3b and the terminal complement complex, as well as with oxidized and modified LDL. 27,34,35 This colocalization suggests a cooperative effect of mCRP and Figure 5 Factor H-mCRP complexes bind phosphocholine. pCRP and mCRP were added to Factor H in solution and the mixture was bound to phosphocholine.…”

“…In this study, we identify PC, which is exposed on the surface of damaged cells, as a ligand for the Factor H-mCRP complex ( Figure 5). 27 CRP binds several complement components and regulators such as C1q. 22 CRP-bound C1q initiates complement activation to the level of the C3 convertase, which results in C3b surface deposition and opsonization.…”

Influence of atherosclerosis‐related risk factors on serum high‐sensitivity C‐reactive protein levels in patients with type 2 diabetes: Comparison of their influence in obese and non‐obese patients

“…It has been thought that serum hs‐CRP level leads to the development of atherosclerosis5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. Although various new pharmacological approaches have been introduced to reduce hs‐CRP levels17, 18, 19, 20, 21, 22, 23, 24, 25, 26, there are still many cardiovascular diseases all over the world.…”

Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis

“…Indeed, CRP can be detected in early lesions of atherosclerosis in humans [20] and its staining intensity correlates with disease development [21]. Moreover, CRP co-localizes with atherogenic mediators, including modified low density lipoproteins (LDL) [22,23], activated complement [24] and foam cells [20]. Together with the reported pro-inflammatory actions of CRP [25,26], including activation of complement and stimulation of expression of cytokines and adhesion molecules in endothelial cells, this protein is emerging as a promising drug target for CVD treatment [16].…”