POS0376 MONOMERIC C REACTIVE PROTEIN (mCRP) REGULATES INFLAMMATORY RESPONSES IN HUMAN AND MOUSE CHONDROCYTES

Background:C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytesObjectives:This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA)Methods:We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target.Results:We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes.Conclusion:mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.References:[1]Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. 2018;9(APR). doi:10.3389/fimmu.2018.00754[2]Francisco V, Pérez T, Pino J, et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: When the levee breaks. J Orthop Res. 2018;36(2):594-604. doi:10.1002/jor.23788[3]Kozijn AE, Tartjiono MT, Ravipati S, et al. Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet. Osteoarthr Cartil. 2019;27(1):118-128. doi:10.1016/j.joca.2018.09.007[4]Rajab IM, Majerczyk D, Olson ME, et al. C-reactive protein in gallbladder diseases: diagnostic and therapeutic insights. Biophys Reports. 2020;6(2-3):49-67. doi:10.1007/s41048-020-00108-9[5]Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396(11):1181-1197. doi:10.1515/hsz-2015-0149[6]Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU. Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes. Mediators Inflamm. 2015;2015(372432):9. doi:10.1155/2015/372432[7]Khreiss T, József L, Hossain S, Chan JSD, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem. 2002;277(43):40775-40781. doi:10.1074/jbc.M205378200[8]Jia ZK, Li HY, Liang YL, Potempa LA, Ji SR, Wu Y. Monomeric C-reactive protein binds and neutralizes receptor activator of NF-κB ligand-induced osteoclast differentiation. Front Immunol. 2018;9(FEB). doi:10.3389/fimmu.2018.00234[9]Francisco V, Ruiz-Fernández C, Pino J, et al. Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases. Biochem Pharmacol. 2019;165:196-206. doi:10.1016/j.bcp.2019.03.030[10]Ullah N, Ma FR, Han J, et al. Monomeric C-reactive protein regulates fibronectin mediated monocyte adhesion. Mol Immunol. 2020;117:122-130. doi:10.1016/j.molimm.2019.10.013[11]Boras E, Slevin M, Alexander MY, et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine. 2014;69(2):165-179. doi:10.1016/j.cyto.2014.05.027Disclosure of Interests:None declared

Download Full-text

The Plasmatic Aldosterone and C-Reactive Protein Levels, and the Severity of Covid-19: The Dyhor-19 Study

Journal of Clinical Medicine ◽

10.3390/jcm9072315 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2315 ◽

Cited By ~ 6

Author(s):

Orianne Villard ◽

David Morquin ◽

Nicolas Molinari ◽

Isabelle Raingeard ◽

Nicolas Nagot ◽

...

Keyword(s):

Inflammatory Responses ◽

Clinical Course ◽

Clinical Status ◽

Plasma Renin ◽

Ordinal Scale ◽

C Reactive Protein ◽

Protein Levels ◽

Reactive Protein

Background. The new coronavirus SARS-CoV-2, responsible for the Covid-19 pandemic, uses the angiotensin converting enzyme type 2 (ACE2), a physiological inhibitor of the renin angiotensin aldosterone system (RAAS), as a cellular receptor to infect cells. Since the RAAS can induce and modulate pro-inflammatory responses, it could play a key role in the pathophysiology of Covid-19. Thus, we aimed to determine the levels of plasma renin and aldosterone as indicators of RAAS activation in a series of consecutively admitted patients for Covid-19 in our clinic. Methods. Plasma renin and aldosterone levels were measured, among the miscellaneous investigations needed for Covid-19 management, early after admission in our clinic. Disease severity was assessed using a seven-category ordinal scale. Primary outcome of interest was the severity of patients’ clinical courses. Results. Forty-four patients were included. At inclusion, 12 patients had mild clinical status, 25 moderate clinical status and 7 severe clinical status. In univariate analyses, aldosterone and C-reactive protein (CRP) levels at inclusion were significantly higher in patients with severe clinical course as compared to those with mild or moderate course (p < 0.01 and p = 0.03, respectively). In multivariate analyses, only aldosterone and CRP levels remained positively associated with severity. We also observed a positive significant correlation between aldosterone and CRP levels among patients with an aldosterone level greater than 102.5 pmol/L. Conclusions. Both plasmatic aldosterone and CRP levels at inclusion are associated with the clinical course of Covid-19. Our findings may open new perspectives in the understanding of the possible role of RAAS for Covid-19 outcome.

Download Full-text

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 ◽

10.3389/fimmu.2018.01351 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 38

Author(s):

James D. McFadyen ◽

Jurij Kiefer ◽

David Braig ◽

Julia Loseff-Silver ◽

Lawrence A. Potempa ◽

...

Keyword(s):

Conformational Changes ◽

Biological Role ◽

C Reactive Protein ◽

Reactive Protein

Download Full-text

C-Reactive Protein Knockout Attenuates Temporomandibular Joint Inflammation in Rats

Journal of Immunology Research ◽

10.1155/2022/8613986 ◽

2022 ◽

Vol 2022 ◽

pp. 1-20

Author(s):

Yao He ◽

Mengjiao Zhou ◽

Zixiang Jian ◽

Lingli Fang ◽

Lan Huang ◽

...

Keyword(s):

Temporomandibular Joint ◽

Macrophage Activation ◽

Quantitative Polymerase Chain Reaction ◽

Osteoclast Differentiation ◽

Joint Inflammation ◽

C Reactive Protein ◽

Beneficial Effects ◽

Reactive Protein ◽

And Control

Background. C-reactive protein (CRP), a biomarker of inflammation, is highly expressed in osteoarthritis- (OA-) related diseases, but its exact role remains unknown. In this study, we evaluated the biological effect of CRP on temporomandibular joint (TMJ) inflammation. Methods. Freund’s complete adjuvant (CFA) was used to induce TMJ inflammation in CRP-knockout (CRP-/-) and control rats. Degenerative changes in the TMJ were compared to elucidate the role of CRP in TMJ inflammation. In addition, inflammatory cytokines, macrophage activation, and osteoclast differentiation were evaluated by real-time quantitative polymerase chain reaction, immunohistochemistry, and tartrate-resistant phosphatase staining to explore the potential regulatory mechanism. Results. Compared to the control, CFA induced TMJ inflammation, which increased systemic and local CRP expression. Furthermore, CRP-/- rats exhibited less severe inflammatory symptoms. The downregulation of proinflammatory cytokines (interleukin- (IL-) 1β and IL-6) and upregulation of the anti-inflammatory cytokine IL-10 were detected in CRP-/- rats, which also exhibited reduced macrophage activation and osteoclast differentiation. Conclusion. These results indicated that controlling the highly elevated levels of CRP during inflammation could modify the cytokine profile, macrophage activation, and osteoclast differentiation, thus, providing beneficial effects for TMJ-OA prevention and treatment.

Download Full-text

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

Mediators of Inflammation ◽

10.1155/2015/372432 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 48

Author(s):

J. R. Thiele ◽

J. Zeller ◽

H. Bannasch ◽

G. B. Stark ◽

K. Peter ◽

...

Keyword(s):

Conformational Changes ◽

Structural Changes ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

C Reactive Protein ◽

Inflammatory Reactions ◽

Reactive Protein ◽

Dissociation Mechanism ◽

Proinflammatory Mediators

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.

Download Full-text

Inflammatory interactions in fish exposed to pollutants and parasites: a role for apoptosis and C reactive protein

Parasitology ◽

10.1017/s0031182003003779 ◽

2003 ◽

Vol 126 (7) ◽

pp. S71-S85 ◽

Cited By ~ 21

Author(s):

D. HOOLE ◽

J. W. LEWIS ◽

P. M. M. SCHUWERACK ◽

C. CHAKRAVARTHY ◽

A. K. SHRIVE ◽

...

Keyword(s):

Inflammatory Response ◽

Inflammatory Responses ◽

Endocrine System ◽

Original Data ◽

C Reactive Protein ◽

Reactive Protein ◽

Ultrastructural Appearance ◽

Two Parameters ◽

Established Infection

Although previous studies have highlighted the inflammatory responses of fish infected with parasites and exposed to pollutants, very little is known about how these two stressors interact within the fish. In this review, which also contains original data, the effect of these two parameters on the fish inflammatory response is assessed and, in particular, the role of apoptosis and the acute phase protein, C reactive protein, is evaluated. InCyprinus carpioexposed to 0·5 mg NH4+l−1or 0·1 mg Cd2+l−1and experimentally infected with the blood fluke,Sanguinicola inermis, the pollutant type and the order in which the fish experiences the parasite and toxicant, significantly affects the ultrastructural appearance and cellular content of the pronephros and thymus. This is reflected in the intensity of infection where the pollutant appears to have less effect on an established infection. Both stressors, pollutant and infection, may mediate their effects via the endocrine system. Studies have revealed that cortisol at 100 ng ml−1is able to induce apoptosis in pronephric cells of carp and that an increase in apoptosis is associated with an increase in phagocytosis in this immune organ. In addition, C reactive protein, which is used as a biomarker of the inflammatory response in humans and other mammals, is evaluated as a possible indicator of physiological states in fish exposed to pathogens and pollutants.

Download Full-text