C-Reactive Protein Mechanisms in Inflammation and Disease

C-reactive protein (CRP) is a central acute-phase protein synthesised predominantly by hepatocytes in response to pro-inflammatory cytokines. In its native form, CRP circulates as a cyclic pentamer (pCRP) that binds phosphocholine residues on damaged cells and pathogens, thereby promoting complement activation and opsonisation. At sites of tissue injury or cellular activation, pCRP undergoes conformational rearrangement into pro-inflammatory isoforms, notably the dissociated monomeric CRP (mCRP) and an intermediate neoepitope-exposing pentameric form (pCRP*). These structural transitions unmask binding sites for complement factor C1q and cell-surface receptors, amplifying leukocyte recruitment, endothelial activation and cytokine release. While pCRP can exert counter-regulatory, anti-inflammatory effects, mCRP is implicated in the propagation of vascular inflammation, thrombosis and autoimmunity. Accumulating evidence links CRP isoforms to a spectrum of conditions—from atherothrombosis and ischaemia–reperfusion injury to neurodegeneration and systemic autoimmune disorders—underscoring its dual role as biomarker and mediator. Targeting the conformational balance of CRP holds promise for innovative therapies aimed at mitigating collateral tissue damage in diverse inflammatory diseases.

Research from Nature Portfolio

Recent studies have elucidated the mechanism by which pCRP interacts with cell-derived microvesicles to form an activated complex (pCRP*) that retains pentameric symmetry yet exposes pro-inflammatory neoepitopes. This form binds complement component C1q, triggering classical complement activation and enhancing leukocyte adhesion to inflamed endothelium. Inhibition of the pCRP–microvesicle interface by small-molecule blockers selectively abrogates these effects, reducing tissue injury in models of myocardial infarction and stroke. These findings provide a structural framework for development of CRP-targeted therapeutics that prevent neoepitope exposure without depleting circulating CRP levels.

C-Reactive Protein Mechanisms in Inflammation and Disease publication trend

The graph below shows the total number of articles in c-reactive protein mechanisms in inflammation and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Pentameric CRP (pCRP): The native cyclic pentameric structure of C-reactive protein found in circulation.

Monomeric CRP (mCRP): A dissociated form of CRP with pro-inflammatory bioactivities.

Conformational isoform: A structurally distinct variant of a protein with altered functional properties.

Extracellular vesicles (EVs): Membrane-bound particles released by cells that can carry proteins, lipids and nucleic acids.

Complement pathway: A cascade of plasma proteins that enhances immune clearance of pathogens and damaged cells.

References

1. Extracellular vesicles opsonized by monomeric C-reactive protein (CRP) are accessible as autoantigens in patients with systemic lupus erythematosus and associate with autoantibodies against CRP. Journal of Autoimmunity (2023).
2. C-reactive protein: a target for therapy to reduce inflammation. Frontiers in Immunology (2023).
3. Monomeric C‐reactive protein: A novel biomarker predicting neurodegenerative disease and vascular dysfunction. Brain Pathology (2023).
4. Role of C-Reactive Protein at Sites of Inflammation and Infection. Frontiers in Immunology (2018).
5. C-Reactive Protein in Atherothrombosis and Angiogenesis. Frontiers in Immunology (2018).
6. Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nature Communications (2017).
7. C-reactive Protein*. Journal of Biological Chemistry (2004).
8. Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes. Frontiers in Immunology (2018).
9. STAT3 Participates in Transcriptional Activation of the C-reactive Protein Gene by Interleukin-6 (∗). Journal of Biological Chemistry (1996).
10. Targeting C‐Reactive Protein in Inflammatory Disease by Preventing Conformational Changes. Mediators of Inflammation (2015).
11. How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression. Frontiers in Immunology (2020).