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. 2021 Sep 23;12:652252. doi: 10.3389/fimmu.2021.652252

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Copyright © 2021 Labarrere and Kassab

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Monomeric C-reactive protein in atherogenesis. [1] From right to left. Monomeric C-reactive protein (mCRP) bound to oxidized/modified (ox/modified) low density lipoprotein (LDL) through lysophosphatidylcholine (LPC) binds Fcγ receptors (Rs) upregulates endothelial tissue factor (TF) (right in 1). Monomeric CRP bound to phosphorylcholine (PC) in lipid rafts activate intracellular signaling cascades (phospholipase C, PLC; p38 mitogen activating protein kinases, MAPK; nuclear factor κB, NFκB) enhancing endothelial intercellular adhesion molecule-1 (ICAM-1) (right in 1). Monocytes/macrophages adhere to endothelium following mCRP-mediated ICAM-1 and CD11b/CD18 (Mac-1) receptor upregulation; mCRP in monocytes/macrophages upregulate TF and Mac-1 and adhere to vitronectin/fibronectin in the intima (right in 1). TF, factor XIIa, fibrinogen and complement participate in thrombus formation and platelets generate further mCRP from nCRP. Interaction among mCRP, glycoprotein (Gp) IIb/IIIa, P-selectin and CD36 participate in inflammation and thrombus formation. Endothelial and platelet microparticles generate mCRP from nCRP and nonnative CRP (nnCRP) (center right in 1). Monomeric CRP facilitates endothelial neutrophil adherence via FcγRIII and Mac-1 upregulation; neutrophil Mac-1 and P-selectin glycoprotein ligand (PSGL)-1 attach to ICAM-1 and P-selectin, respectively; mCRP- FcγRIII enhance peroxinitrite (ONOO^-) generation, NFκB activation and IL-8 and monocyte chemoattractant protein-1 (MCP-1) release (center in 1). Endothelial phospholipase A₂ (PLA₂) generates LPC facilitating monomerization of CRP that binds lipid rafts and FcγRIII and activates NFκB/p38MAPK, upregulating plasminogen activator inhibitor (PAI)-1, vascular cell adhesion molecule (VCAM)-1, E-selectin and endothelin-1; downregulating endothelial nitric oxide synthase (eNOS) and nitric oxide (NO); and enhancing IL-8 and MCP-1 release (left and center left in 1). [2] CRP via FcαRI and mCRP via FcγRIIIb can activate phosphatidylinositol 3-kinases/protein kinase B and extracellular signal-regulated kinases (PI3k/AKT, ERK) signaling pathways in intimal neutrophils and enhance tumor necrosis factor-α (TNF-α) release and delay apoptosis. T-cells can produce CRP enhancing intimal CRP. [3] Mast cells contribute to oxLDL macrophage uptake through TNF-α, interferon-γ (IFN-γ), IL-6 and heparin secretion. CRP can be synthesized by smooth muscle cells (SMC) and foam cells, and FcγRIIIa-bound mCRP in SMCs induce ROS and upregulate TF enhancing thrombus formation through factor VII activation; mCRP can upregulate angiotensin (AT)₁R and ATII-mediated ROS production. [4] LRP-1/CD91 and scavenger receptors facilitate collectin- and oxLDL-like site-mediated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uptake, respectively, and FcγRs can facilitate nCRP and mCRP-mediated SARS-CoV-2 macrophage phagocytosis; mCRP and ICAM-1 can mediate ROS formation and subsequent release of IL-8, MCP-1, IL-6, TNF-α and matrix metalloproteinases (MMPs). [5] Increased ROS formation, reduced glutathione (GSH) and glutathione peroxidase (GPx)-1 activity increase foam cell formation sustaining inflammation in the plaque (center in 5). OxLDL bound to IgM natural antibodies (NAbs) can block Fcα/μ-mediated oxLDL uptake. Monomeric CRP bound to lipid rafts, LPC, PC or FcγRs and LPC-bound nonnative CRP (nnCRP) could enhance ROS formation; and LPC bound mCRP activate C1q (lower left in 5). CRP/CD32 and LDL-R facilitate macrophage LDL uptake (center left in 5). CRP bound to CD64 enhance oxLDL uptake and foam cell formation; mCRP contributes to intimal inflammation, integrin-mediated TF upregulation and chemotaxis and C1q activation (upper left in 5). 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,facilitate oxLDL macrophage uptake; and FcγRs CRP-bound oxLDL and oxLDL immune complexes (oxLDL-ICs) (upper center and upper right in 5). LPC membrane-bound nCRP dissociates into mCRP with intermediate nnCRP formation, and mCRP can induce myeloperoxidase (MPO) synthesis and release; LPC- and lipid raft-bound mCRP can enhance ROS formation (right in 5). Monomeric CRP bound to CD16 or LPC can enhance foam cell ROS (right in 5).