Targeting C‐Reactive Protein in Inflammatory Disease by Preventing Conformational Changes

Abstract

C-reactive protein (CRP) is a pentraxin that has long been employed as a marker of inflammation in clinical practice. Recent findings brought up the idea of CRP to be not only a systemic marker but also a mediator of inflammation. New studies focused on structural changes of the plasma protein, revealing the existence of two distinct protein conformations associated with opposed inflammatory properties. Native, pentameric CRP (pCRP) is considered to be the circulating precursor form of monomeric CRP (mCRP) that has been identified to be strongly proinflammatory. Recently, a dissociation mechanism of pCRP has been identified on activated platelets and activated/apoptotic cells associated with the amplification of the proinflammatory potential. Correspondingly, CRP deposits found in inflamed tissues have been identified to exhibit the monomeric conformation by using conformation-specific antibodies. Here we review the current literature on the causal role of the dissociation mechanism of pCRP and the genesis of mCRP for the amplification of the proinflammatory potential in inflammatory reactions such as atherosclerosis and ischemia/reperfusion injury. The chance to prevent the formation of proinflammatory mediators in ubiquitous inflammatory cascades has pushed therapeutic strategies by targeting pCRP dissociation in inflammation. In this respect, the development of clinically applicable derivatives of the palindromic compound 1,6-bis(phosphocholine)-hexane (1,6-bis PC) should be a major focus of future CRP research.

Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain

“…As shown here in LBP, systemic CRP concentrations relate to pain/disease severity [18,85,105]. However, involvement of CRP in underlying pathological processes has been debated [5,123] because it has both pro-and anti-inflammatory effects [107]. These have been reported separately [6,82] and explained by two distinct CRP structural forms associated with opposite inflammatory properties [34].…”

“…These have been reported separately [6,82] and explained by two distinct CRP structural forms associated with opposite inflammatory properties [34]. Under inflammatory conditions circulating (native) CRP can dissociate into a pro-inflammatory and predominantly tissuebound form of CRP [34,107,119]. Prevention of this dissociation has therapeutic benefit (inhibition of pro-inflammatory effects) in a rat model [83].…”

The combination of CRP isoforms with oxLDL decreases TNF-α and IL-6 release by U937-derived macrophages

“…However, additional in vivo and in vitro studies are required to investigate the effects of this combination either on the arteries or on other cell types that have crucial roles in plaque development. Recent studies have been targeting pCRP dissociation as a novel therapy for atherosclerosis (34).…”

An Intrinsically Disordered Motif Mediates Diverse Actions of Monomeric C-reactive Protein

“…Accumulating evidence demonstrates that the actions of CRP depend on conformation and localization (3)(4)(5). CRP is primarily produced by the liver and circulates in the blood as a pentamer but is induced to dissociate into subunits (monomeric CRP, mCRP) upon interaction with the microenvironment at inflammatory loci (6 -18).…”

“…The differential contributions of these CRP conformations at distinct locations may therefore account for the intense controversies regarding the function of CRP in animal models and in clinical studies (3)(4)(5). mCRP appears to be the major conformation of CRP that regulates local inflammation (3)(4)(5), yet how it acts remains incompletely understood. In particular, though the markedly enhanced binding capability of mCRP underlies its actions, little is known through which sites mCRP recognizes diverse ligands.…”