title: The role of C-reactive protein in innate and acquired inflammation: new perspectives.
abstract: The participation of C-reactive protein (CRP) in host defense against microorganisms has been well described. More controversial has been its role in chronic conditions such as cardiovascular disease. Our recent publications explain the reasons for some of the confusion concerning CRP as a risk factor for disease and whether it is pro-inflammatory or anti-inflammatory. We found that two isoforms of CRP, pentameric (pCRP) and monomeric (mCRP), on microparticles (MPs), were not measureable by standard clinical assays. When we investigated MPs by imaging cytometry in plasma from controls versus patients with peripheral artery disease, we found that MPs from endothelial cells bearing mCRP were elevated. This elevation did not correlate with the soluble pCRP measured by high-sensitivity CRP assays. The data suggest that detection of mCRP on MPs may be a more specific marker in diagnosis, measurement of progression, and risk sensitivity in chronic disease. In an in vitro model of vascular inflammation, pCRP was anti-inflammatory and mCRP was pro-inflammatory for macrophage and T cell polarization. When we further investigated pCRP under defined conditions, we found that pCRP in the absence of a phosphocholine ligand had no inflammatory consequences. When combined with phosphocholine ligands, pCRP signaled through two Fcγ receptors (FcγRI and FcγRII) via phosphorylation of spleen tyrosine kinase (pSYK) to activate monocytes. Phosphocholine itself, when bound to pCRP, induced a congruent M2 macrophage and Th2 response. Phosphocholine is also the head group on the lipid phosphatidylcholine, which can become oxidized. Liposomes bearing oxidized phosphatidylcholine without pCRP promoted a uniform M1 macrophage and Th1 pro-inflammatory response. When oxidized liposomes were bound to pCRP, there was a disjunction in the macrophage and T cell response: monocytes matured into M2 macrophages, but the T cells polarized into a Th1 phenotype. The CRP-bound liposomes signaled monocytes via FcγRII to promote an anti-inflammatory M2 macrophage state, whereas the lack of FcγR on T cells allowed their liposome-induced polarization to a pro-inflammatory Th1 phenotype unopposed by the contribution of the pCRP/FcγR interaction. Different isoforms of CRP and its binding to complex ligands may determine its biological activities and their contribution to inflammatory states.
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trial
authors.affiliation: College of Pharmacy, Roosevelt University, Schaumburg, Illinois, 60173, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Potempa
authors.affiliation: Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
keywords: C-reactive protein; hsCRP assay; macrophage polarization