Figure 6.

C-reactive protein innate immunoprotective responses in atherosclerotic lesions. [1] Native pentameric C-reactive protein (nCRP) and CRP peptides prevent neutrophil adhesion by downregulating L-selectin expression through activation of Fcγ receptor (R) IIa and immunoreceptor tyrosine-based activation motif (ITAM), and by inducing L-selectin shedding; nCRP downregulates CD11b/CD18 (Mac-1) receptor activation and endothelial intercellular adhesion molecule-1 (ICAM-1) expression (right in 1). Native pentameric CRP induces FcγR-mediated interleukin (IL)-1 receptor antagonist (Ra) expression in mononuclear cells (middle in 1). CRP bound to oxLDL can reduce endothelial nitric oxide synthase (eNOS) through FcγRs and immunoreceptor tyrosine-based inhibitory motif (ITIM) activation (middle in 1). Circulating nCRP bound to cellular or microparticle lysophosphatidylcholine (LPC) generated by phospholipase A₂ (PLA₂), or to phosphorylcholine (PC) can be dissociated to monomeric CRP (mCRP) with intermediate formation of non-native CRP (nnCRP), and mCRP can bind lipid rafts and increase reactive oxygen species (ROS) formation (left in 1). Native CRP can prevent cell damage by enhancing membrane-bound expression of complement regulators decay-accelerating factor (DAF), membrane cofactor protein (CD46) and CD59 mediated by transcription factor (nuclear factor kappa B, NFκB; activator protein 1, AP-1; mitogen-activated protein kinases, MAPKs) activation. [2] The clearance of apoptotic cells is facilitated by immunoglobulin M anti-oxidation specific epitopes natural antibodies (IgM anti-OSE NAbs) and Fcα/μRs; nCRP-PC, complement 1q (C1q), factor H and FcγRIIa; and nCRP-phosphatidylserine (PS) and FcγRIIa, respectively. Low-density lipoproteins (LDL) uptake occurs via LDL-Rs. [3] Native CRP downregulates Mac-1 activation. Native CRP, C1q and factor H; collectins bound to low density lipoprotein receptor-related protein (LRP)-1/CD91; and oxLDL-like sites bound to scavenger receptors facilitate efferocytosis. CRP bound to PC and FcγRI induces M2 macrophage differentiation that reduces inflammation through IL-10 and IL-1R antagonist (IL1Ra) secretion. Th2 T-lymphocytes release IL-4 further inducing M2 macrophages. CRP binds FcαRI facilitating transforming growth factor-ß (TGF-ß) release and phagocytosis. FcγRs CD32 and CD64, scavenger receptor CD36, FcγRIIa R131 and Fcα/μR facilitate clearance of oxidized/modified LDL. [4] FcαRI mediates nCRP neutrophil stimulation of phagocytosis. [5] Immunoglobulin M (IgM) anti oxidation-specific epitopes (OSE) blocks scavenger receptors lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), scavenger receptor class B type 1 (SR-BI), scavenger receptor A1 (SR-A1) and CD36 inhibiting oxLDL uptake. Native CRP through CD32 and immunoreceptor tyrosine-based inhibitory motif (ITIM) inhibits oxLDL uptake; and through CD64 binding induces M2 macrophage differentiation that enhances release of IL-10, TGF-ß and arginase 1. [6] Clearance of oxidized/modified LDL, inhibition of oxLDL uptake, clearance of apoptotic cells, reduced reactive oxygen species (ROS) and reduced oxLDL formation associated with increased glutathione (GSH) and glutathione peroxidase-1 (GPx-1) activity contribute to reduced foam cell formation.