C-reactive protein: a target for therapy to reduce inflammation

Abstract

C-reactive protein (CRP) is well-recognized as a sensitive biomarker of inflammation. Association of elevations in plasma/serum CRP level with disease state has received considerable attention, even though CRP is not a specific indicator of a single disease state. Circulating CRP levels have been monitored with a varying degree of success to gauge disease severity or to predict disease progression and outcome. Elevations in CRP level have been implicated as a useful marker to identify patients at risk for cardiovascular disease and certain cancers, and to guide therapy in a context-dependent manner. Since even strong associations do not establish causality, the pathogenic role of CRP has often been over-interpreted. CRP functions as an important modulator of host defense against bacterial infection, tissue injury and autoimmunity. CRP exists in conformationally distinct forms, which exhibit distinct functional properties and help explaining the diverse, often contradictory effects attributed to CRP. In particular, dissociation of native pentameric CRP into its subunits, monomeric CRP, unmasks "hidden" pro-inflammatory activities in pentameric CRP. Here, we review recent advances in CRP targeting strategies, therapeutic lowering of circulating CRP level and development of CRP antagonists, and a conformation change inhibitor in particular. We will also discuss their therapeutic potential in mitigating the deleterious actions attributed to CRP under various pathologies, including cardiovascular, pulmonary and autoimmune diseases and cancer.

Keywords: C-reactive protein; CRP antagonists; CRP lowering therapies; autoimmunity; cancer; cardiovascular disease; inflammation; monomeric CRP.

Figure 1

Proposed model for regulation of the inflammatory response by conformationally distinct CRP isomers. In the circulation, native CRP exists in a disc-shaped pentameric form (pCRP) and exhibits predominantly anti-inflammatory activities (e.g. opsonization) that are critical for clearance of invading bacteria and damaged cells by phagocytes. Thus, pCRP may limit further damage and prevent autoimmunity. Mild acidosis within the inflammatory locus unmasks additional binding sites in pCRP for complement factor H, which modulate coagulation and for conformationally altered proteins, thereby promoting their removal. Binding of pCRP to phosphocholine or phosphoethanolamine head groups exposed on the surface of activated or damaged cells, or microvesicles, leads to formation of a partially dissociated pentamer (pCRP*) followed by dissociation into its monomeric subunits (mCRP). Unlike pCRP, pCRP*/mCRP exhibit potent pro-inflammatory actions, including stimulation of thrombus formation, activation of endothelial cells, monocytes, platelets and neutrophils, neutrophil and monocyte adhesion to endothelial cells, enhanced formation of neutrophil-platelet and platelet-monocyte aggregates, production of pro-inflammatory cytokines IL-1β and IL-6, and extrusion of neutrophil extracellular traps (NET). These may contribute to excessive, non-resolving inflammation and to aggravation of tissue injury. This multistep mechanism would uncouple the local effects of pCRP*/mCRP from those of circulating pCRP, therefore contribute to localization of inflammation. Of note, microvesicle-associtaed pCRP*/mCRP may contribute spreading the inflammatory reaction to distant sites. EC, endothelial cells; mCRP, monomeric CRP; NETosis, extrusion of neutrophil extracellular traps; pCRP, pentameric CRP; pCRP*, partially dissociated pentameric CRP; PMN, polymorphonuclear neutrophil granulocytes. Modified from Wu et al. (21) and Filep (54).