C-reactive Protein in Inflammatory Diseases: Clinical Aspects

Topic Information

Dear Colleagues,

This Topic focuses on the clinical relevance of C-reactive protein. Most physicians are familiar with it as a diagnostic biomarker, but only a few have realised that it can be a pathomolecule. After all, biomarker is of course not a physiological function. The main task of CRP is to mark cells to be disposed of, which has been shown for decades in various animal models and has been broken down to the molecular level. For several decades, CRP has been established as an extremely sensitive, reliable and early indicator of inflammatory and tissue-destructive processes. Following an acute phase stimulus, up to 1000-fold increased values can be measured.

This prototype of the human acute phase protein has been considered an inflammatory marker since it was first described by Tillet and Francis in 1930.

However, the mere use of CRP as a readily measurable inflammation marker neglects the biological function of the protein.

CRP is a serum protein and a mediator of innate immunity. The diverse functions of CRP across all living species led to the conclusion that CRP is a prehistoric precursor of all antibodies in the evolutionarily much-later-appearing mammals.

Already in the horseshoe crab (Limulus), a “living fossil” at least 250 million years old, CRP forms immune complexes together with the complement system and thus assumes defence functions. At the same time, it acts phylogenetically as an antibody in numerous species, such as fish, which have no adaptive immune system. In humans, its functions are complex and part of re-intensified research.

It is now accepted, even if not everyone is aware of it, that CRP plays a central role in the development of inflammation-related tissue damage. CRP activates (in the manner of antibodies) the complement system via the classical pathway and macrophages via Fc receptors. Therefore, CRP, in the manner of antibodies, binds to Fc receptors.

The present Topic aims to provide an overview of relevant studies and provide an outlook into the future perspective on this pivotal protein. This will not only provide valuable information on the potential for CRP-driven prognostic decisions, but also identify obstacles that need to be overcome to address CRP therapeutically.

Dr. Ahmed Sheriff
Prof. Dr. Jan Torzewski
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Clinics and Practice clinpract	1.7	2.6	2011	20.8 Days	CHF 1600
Diagnostics diagnostics	3.0	4.7	2011	20.3 Days	CHF 2600
Journal of Clinical Medicine jcm	3.0	5.7	2012	16 Days	CHF 2600
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900

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Published Papers (5 papers)

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All Biomedicines Clinics and Practice Diagnostics JCM Pharmaceuticals

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12 pages, 3714 KiB  

Open AccessArticle

Sulfated CXCR3 Peptide Trap Use as a Promising Therapeutic Approach for Age-Related Macular Degeneration

by Gukheui Jo, Jae-Byoung Chae, Sun-Ah Jung, Jungmook Lyu, Hyewon Chung and Joon H. Lee

Biomedicines 2024, 12(1), 241; https://doi.org/10.3390/biomedicines12010241 - 22 Jan 2024

Cited by 2 | Viewed by 2160

Abstract

Background and Objectives: Chemokines have various biological functions and potential roles in the development or progression of neuroinflammatory diseases. However, the specific pathogenic roles of chemokines in the major cause for vision loss among the elderly, the leading cause of blindness in older [...] Read more.

Background and Objectives: Chemokines have various biological functions and potential roles in the development or progression of neuroinflammatory diseases. However, the specific pathogenic roles of chemokines in the major cause for vision loss among the elderly, the leading cause of blindness in older individuals, remain elusive. Chemokines interact with their receptors expressed in the endothelium and on leukocytes. The sulfation of tyrosine residues in chemokine receptors increases the strength of ligand–receptor interaction and modulates signaling. Therefore, in the present study, we aimed to construct a human recombinant sulfated CXCR3 peptide trap (hCXCR3-S2) and mouse recombinant sulfated CXCR3 peptide trap (mCXCR3-S2) to demonstrate in vivo effects in preventing choroidal neovascularization (CNV) and chemotaxis. Materials and Methods: We generated expression vectors for mCXCR3-S2 and hCXCR3-S2 with GST domains and their respective cDNA sequences. Following overexpression in E. coli BL21 (DE3), we purified the fusion proteins from cell lysates using affinity chromatography. First, the impact of hCXCR3-S2 was validated in vitro. Subsequently, the in vivo efficacy of mCXCR3-S2 was investigated using a laser-induced CNV mouse model, a mouse model of neovascular age-related macular degeneration (AMD). Results: hCXCR3-S2 inhibited the migration and invasion of two human cancer cell lines. Intravitreal injection of mCXCR3-S2 attenuated CNV and macrophage recruitment in neovascular lesions of mouse models. These in vitro and in vivo effects were significantly stronger with CXCR3-S2 than with wild-type CXCR3 peptides. Conclusion: These findings demonstrate that the sulfated form of the CXCR3 peptide trap is a valuable tool that could be supplemented with antivascular endothelial growth factors in AMD treatment. Full article

(This article belongs to the Topic C-reactive Protein in Inflammatory Diseases: Clinical Aspects)

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17 pages, 1204 KiB  

Open AccessArticle

Diabetes Status, c-Reactive Protein, and Insulin Resistance in Community-Acquired Pneumonia—A Prospective Cohort Study

by Arnold Matovu Dungu, Camilla Koch Ryrsø, Maria Hein Hegelund, Andreas Vestergaard Jensen, Peter Lommer Kristensen, Rikke Krogh-Madsen, Christian Ritz, Daniel Faurholt-Jepsen and Birgitte Lindegaard

J. Clin. Med. 2024, 13(1), 245; https://doi.org/10.3390/jcm13010245 - 31 Dec 2023

Cited by 2 | Viewed by 1753

Abstract

C-reactive protein (CRP) is commonly used to guide community-acquired pneumonia (CAP) treatment. A positive association between admission glucose and CRP levels has been observed in patients with CAP. The associations between prediabetes, unknown diabetes, acute-on-chronic hyperglycaemia, and CRP levels, and between admission CRP [...] Read more.

C-reactive protein (CRP) is commonly used to guide community-acquired pneumonia (CAP) treatment. A positive association between admission glucose and CRP levels has been observed in patients with CAP. The associations between prediabetes, unknown diabetes, acute-on-chronic hyperglycaemia, and CRP levels, and between admission CRP levels and insulin resistance (IR) in CAP, remain unexplored. This study investigated the associations firstly between chronic, acute, and acute-on-chronic hyperglycaemia and CRP levels, and secondly between admission CRP levels and IR in CAP. In a prospective cohort study of adults with CAP, the associations between chronic, acute, and acute-on-chronic hyperglycaemia (admission glucose minus HbA1c-derived average glucose) and CRP levels until admission day 3 were modelled with repeated-measures linear mixed models. IR was estimated with the homeostasis model assessment of IR (HOMA-IR). The association between admission CRP levels and HOMA-IR was modelled with linear regression. In 540 patients, no association between chronic, acute, or acute-on-chronic hyperglycaemia and CRP levels was found. In 266 patients, every 50 mg/L increase in admission CRP was associated with a 7% (95% CI 1–14%) higher HOMA-IR. In conclusion, our findings imply that hyperglycaemia does not influence CRP levels in patients with CAP, although admission CRP levels were positively associated with IR. Full article

(This article belongs to the Topic C-reactive Protein in Inflammatory Diseases: Clinical Aspects)

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12 pages, 1078 KiB  

Open AccessPerspective

Being Eaten Alive: How Energy-Deprived Cells Are Disposed of, Mediated by C-Reactive Protein—Including a Treatment Option

by Ahmed Sheriff, Rudolf Kunze, Patrizia Brunner and Birgit Vogt

Biomedicines 2023, 11(8), 2279; https://doi.org/10.3390/biomedicines11082279 - 16 Aug 2023

Cited by 4 | Viewed by 2132

Abstract

In medicine, C-reactive protein (CRP) has become established primarily as a biomarker, predicting patient prognosis in many indications. Recently, however, there has been mounting evidence that it causes inflammatory injury. As early as 1999, CRP was shown to induce cell death after acute [...] Read more.

In medicine, C-reactive protein (CRP) has become established primarily as a biomarker, predicting patient prognosis in many indications. Recently, however, there has been mounting evidence that it causes inflammatory injury. As early as 1999, CRP was shown to induce cell death after acute myocardial infarction (AMI) in rats and this was found to be dependent on complement. The pathological effect of CRP was subsequently confirmed in further animal species such as rabbit, mouse and pig. A conceptual gap was recently closed when it was demonstrated that ischemia in AMI or ischemia/hypoxia in the severe course of COVID-19 causes a drastic lack of energy in involved cells, resulting in an apoptotic presentation because these cells cannot repair/flip-flop altered lipids. The deprivation of energy leads to extensive expression on the cell membranes of the CRP ligand lysophosphatidylcholine. Upon attachment of CRP to this ligand, the classical complement pathway is triggered leading to the swift elimination of viable cells with the appearance of an apoptotic cell by phagocytes. They are being eaten alive. This, consequently, results in substantial fibrotic remodeling within the involved tissue. Inhibiting this pathomechanism via CRP-targeting therapy has been shown to be beneficial in different indications. Full article

(This article belongs to the Topic C-reactive Protein in Inflammatory Diseases: Clinical Aspects)

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13 pages, 1958 KiB  

Open AccessArticle

Discrepancy of C-Reactive Protein, Procalcitonin and Interleukin-6 at Hospitalization: Infection in Patients with Normal C-Reactive Protein, Procalcitonin and High Interleukin-6 Values

by Eun-Hwa Lee, Kyoung-Hwa Lee, Young-Goo Song and Sang-Hoon Han

J. Clin. Med. 2022, 11(24), 7324; https://doi.org/10.3390/jcm11247324 - 9 Dec 2022

Cited by 9 | Viewed by 3490

Abstract

C-reactive protein (CRP) or procalcitonin (PCT) alone has limitations in the early detection of infection or inflammation due to shortcomings in specificity and varied cut-off values. Recently, interleukin (IL)-6 has been assessed, but it is not known to what extent the three values [...] Read more.

C-reactive protein (CRP) or procalcitonin (PCT) alone has limitations in the early detection of infection or inflammation due to shortcomings in specificity and varied cut-off values. Recently, interleukin (IL)-6 has been assessed, but it is not known to what extent the three values are homogeneous in reality. This retrospective study was conducted with two large datasets (discrepancy set with results within 24 h of admission [7149 patients] and follow-up set until 2 weeks of hospital stay [5261 tests]) consisting of simultaneous examinations of CRP, PCT, and IL-6 between January 2015 and August 2021. The specific discrepant group (n = 102, 1.4%) with normal CRP (<10 mg/L) and PCT (<0.1 ng/mL) and high IL-6 (≥100 pg/mL) values was extracted from the discrepancy set. Dimensionality reduction and visualization were performed using Python. The three markers were not clearly clustered after t-distributed stochastic neighbor embedding. Pearson’s correlation coefficients between two markers were substantially low (0.23–0.55). Among the high normalized IL-6 levels (≥0.5) (n = 349), 17.8% and 38.7% of CRP and PCT levels were very low (≤0.01). 9.2% and 13.4% of normal CRP (n = 1522) had high PCT (≥0.5 ng/mL) and IL-6 (≥100 pg/mL) values, respectively. Infection and bacteremia among 102 patients occurred in 36 (35.3%) and 9 (8.8%) patients, respectively. In patients with bacteremia, IL-6 was the first to increase, followed by PCT and CRP. Our study revealed that CRP, PCT, and IL-6 levels were considerably discrepant, which could be misinterpreted if only CRP tests are performed. Full article

(This article belongs to the Topic C-reactive Protein in Inflammatory Diseases: Clinical Aspects)

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8 pages, 1138 KiB  

Open AccessArticle

Sustainability of C-Reactive Protein Apheresis in Acute Myocardial Infarction—Results from a Supplementary Data Analysis of the Exploratory C-Reactive Protein in Acute Myocardial Infarction-1 Study

by Horst Skarabis, Jan Torzewski, Wolfgang Ries, Franz Heigl, Christoph D. Garlichs, Rudolf Kunze and Ahmed Sheriff

J. Clin. Med. 2022, 11(21), 6446; https://doi.org/10.3390/jcm11216446 - 31 Oct 2022

Cited by 4 | Viewed by 2741

Abstract

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) [...] Read more.

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3–9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS). Compared with the control group (n = 34), cardiac damage was significantly lower in the apheresis group (n = 32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65–177) d whether the effect of CRP apheresis is clinically maintained. After this time period, wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of <0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of >0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (−5.4%; p = 0.05), a better LVEF (+6.4%; p = 0.03), and an improved CS (−6.1%; p = 0.005). No significant improvement, however, was observed for LS (−2.9%; p = 0.1). These data suggest a sustained positive effect of CRP apheresis on heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue. Full article

(This article belongs to the Topic C-reactive Protein in Inflammatory Diseases: Clinical Aspects)

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