A biofunctional review of C-reactive protein (CRP) as a mediator of inflammatory and immune responses: differentiating pentameric and modified CRP isoform effects

Abstract

C-reactive protein (CRP) is an acute phase, predominantly hepatically synthesized protein, secreted in response to cytokine signaling at sites of tissue injury or infection with the physiological function of acute pro-inflammatory response. Historically, CRP has been classified as a mediator of the innate immune system, acting as a pattern recognition receptor for phosphocholine-containing ligands. For decades, CRP was envisioned as a single, non-glycosylated, multi-subunit protein arranged non-covalently in cyclic symmetry around a central void. Over the past few years, however, CRP has been shown to exist in at least three distinct isoforms: 1.) a pentamer of five identical globular subunits (pCRP), 2.) a modified monomer (mCRP) resulting from a conformational change when subunits are dissociated from the pentamer, and 3.) a transitional isoform where the pentamer remains intact but is partially changed to express mCRP structural characteristics (referred to as pCRP* or mCRPm). The conversion of pCRP into mCRP can occur spontaneously and is observed under commonly used experimental conditions. In careful consideration of experimental design used in published reports of in vitro pro- and anti-inflammatory CRP bioactivities, we herein provide an interpretation of how distinctive CRP isoforms may have affected reported results. We argue that pro-inflammatory amplification mechanisms are consistent with the biofunction of mCRP, while weak anti-inflammatory mechanisms are consistent with pCRP. The interplay of each CRP isoform with specific immune cells (platelets, neutrophils, monocytes, endothelial cells, natural killer cells) and mechanisms of the innate immune system (complement), as well as differences in mCRP and pCRP ligand recognition and effector functions are discussed. This review will serve as a revised understanding of the structure-function relationship between CRP isoforms as related to inflammation and innate immunity mechanisms.

Hydrogel dressings for diabetic foot ulcer: A systematic review and meta‐analysis

“…In the inflammatory phase, IL‐6 can promote fibroblast proliferation and collagen synthesis 33 . In DFU patients, when CRP levels are elevated, this kind of protein can promote platelet aggregation, stimulate neutrophil chemotaxis and phagocytosis, and activate the release of cytokines, promoting inflammation and limiting the inflammatory response in the damaged area 34 . Both IL‐6 and CRP are inflammatory markers that can be used to monitor inflammation 35 .…”

Monomeric C-reactive protein as a biomarker for major depressive disorder

“…As a soluble oligo-protein that increases exponentially in response to acute infection or injury, pCRP has historically been used as a non-specific biomarker of inflammation in acute or chronic diseases (21,22). This circulating pCRP has been shown to have weak anti-inflammatory functions -decreasing phospholipase A 2 , platelet adhesion factorinduced aggregation of platelets, neutrophil-platelet and-neutrophil adhesion, and decreasing monocyte iNOS production (20,23). Upon interaction with damaged membranes, however, pCRP binds to lysophophatidylcholine, initiating conversion of pCRP to the intermediary pCRP*/mCRP m isoform and, subsequently, mCRP (24)(25)(26).…”

“…Unlike pCRP, mCRP is insoluble in the blood unless protein-or membrane-bound and functions as a pro-inflammatory mediator. mCRP has been shown to increase expression and release of thromboxane A 2 , P-selectin, adhesion molecules, reactive oxygen species, IL-1, IL-6, IL-8 and TNFα (20). In the brain, mCRP has mainly been investigated with respect to infarcts and Alzheimer's disease (AD).…”

“…Given the current lack of studies directly measuring mCRP in MDD, we can only estimate high levels of mCRP in previous MDD studies indirectly by looking at downstream inflammatory markers that are typically enhanced due to mCRP. mCRP increases the expression and release of adhesion molecules and pro-inflammatory cytokines IL-1, IL-6, IL-8, and TNFα (20). In a meta-analysis by Howren et al, positive associations were found between depression and IL-1, IL-6 and CRP (47).…”

“…One aspect that has not been investigated, but may help to clarify the relationship, is the concept of utilizing different CRP isoforms. While CRP was initially identified and described as a pentamer with five homologous subunits, it has since been recognized that the protein exists in three distinct isoforms: (1) pentameric CRP (pCRP), (2) monomeric CRP (mCRP) in which a conformational change dissociates the individual subunits from the pentamer, and (3) an intermediary pentameric form that expresses some of the monomeric structural characteristics (pCRP*/mCRP m ) (20). Each of these isoforms have unique anti-inflammatory or pro-inflammatory functions.…”