Does High Crp Reading Indicate Weak Imune System
Front Immunol. 2018; 9: 754.
Office of C-Reactive Protein at Sites of Inflammation and Infection
Received 2017 Dec 18; Accepted 2018 Mar 26.
Abstract
C-reactive protein (CRP) is an acute inflammatory protein that increases upwardly to ane,000-fold at sites of infection or inflammation. CRP is produced every bit a homopentameric protein, termed native CRP (nCRP), which tin irreversibly dissociate at sites of inflammation and infection into five carve up monomers, termed monomeric CRP (mCRP). CRP is synthesized primarily in liver hepatocytes but as well by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Evidence suggests that estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilized equally a marker of infection and cardiovascular events, in that location is at present growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release, and the production of cytokines, particularly interleukin-6 and tumor necrosis gene-α. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was frequently non specified which particular CRP isoform was measured or utilized in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to acquit studies investigating the mCRP isoform. Despite these issues and the fact that most CRP research to date has focused on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis, and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and tin delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production, respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-eight and monocyte chemoattractant poly peptide-ane production, whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and to fully characterize the differential roles that each CRP isoform plays at sites of local inflammation and infection.
Keywords: C-reactive poly peptide, native C-reactive poly peptide, monomeric C-reactive protein, inflammation, infection
C-Reactive Poly peptide (CRP)
C-reactive protein is a homopentameric acute-stage inflammatory protein, a highly conserved plasma protein that was initially discovered in 1930 by Tillet and Francis while investigating the sera of patients suffering from the acute phase of Pneumococcus infection and was named for its reaction with the capsular (C)-polysaccharide of Pneumococcus (1). In the presence of calcium, CRP binds to polysaccharides such as phosphocholine (PCh) on microorganisms and triggers the classical complement pathway of innate immunity by activating C1q (two). CRP has many homologs in vertebrates and some invertebrates (3) and is a member of the pentraxin family, which includes other structurally related molecules such as serum amyloid A (four). Transcriptional induction of the CRP gene mainly occurs in hepatocytes in the liver in response to increased levels of inflammatory cytokines, specially interleukin-half dozen (IL-half dozen) (5).
C-reactive protein exhibits elevated expression during inflammatory weather such as rheumatoid arthritis, some cardiovascular diseases, and infection (6). As an astute-phase protein, the plasma concentration of CRP deviates by at least 25% during inflammatory disorders (7). The highest concentrations of CRP are found in serum, with some bacterial infections increasing levels up to 1,000-fold (8). However, when the stimuli ends, CRP values subtract exponentially over eighteen–20 h, close to the half-life of CRP (9). CRP plasma levels increase from around 1 µg/mL to over 500 µg/mL within 24–72 h of severe tissue harm such as trauma and progressive cancer (10). IL-6 is reported to be the primary inducer of CRP gene expression, with IL-i enhancing the result (11). Yet, although IL-vi is necessary for CRP cistron induction, information technology is not sufficient to reach this alone (12).
There are many factors that can modify baseline CRP levels including age, gender, smoking status, weight, lipid levels, and blood pressure (13). The average levels of CRP in serum in a healthy Caucasian is effectually 0.8 mg/Fifty, but this baseline can vary greatly in individuals due to other factors, including polymorphisms in the CRP cistron (14). The human CRP gene can be found at 1q23.2 on the long arm of chromosome one, and to date, in that location have been no allelic variations or genetic deficiencies discovered for this factor although some polymorphisms take been identified (13). For case, up to 50% of baseline variance in CRP is associated with the number of dinucleotide repeats found in an intronic region of the factor (15).
At that place is no significant seasonal variation in baseline CRP concentration; however, twin studies show a significant heritable component in baseline CRP values that is independent of age and body mass index (16). Pankow et al. (17) establish evidence that interindividual variation in blood CRP levels is 35–40% heritable. Increased CRP levels are typically associated with disease, but liver failure is 1 condition observed to impair CRP production. Very few drugs reduce elevated CRP levels unless they treat the underlying pathology that is causing the acute-phase stimulus (xvi).
At that place is emerging research that oral hormone replacement therapy (HRT) causes background levels of circulating CRP to increase in postmenopausal women, increasing the gamble of thrombotic events such every bit clots (18). Corcoran et al. (19) found that a combination of estrogen and oxidized depression-density lipoproteins (oxLDLs) increased CRP expression in a model of coronary heart illness in both older men and postmenopausal women, but no result on CRP expression was seen when estrogen supplementation was replaced with testosterone. Ridker et al. (twenty) found that salubrious postmenopausal women had nearly twofold increased levels of circulating CRP when they were taking oral HRT and that CRP was the nearly afflicted inflammatory mark. Numerous studies have confirmed that CRP is a predictive marker for cardiovascular illness and that HRT use in postmenopausal women increases the risk of stroke and blood clots (xx–23).
Interestingly the mode of HRT delivery appears to influence the upshot on circulating CRP levels. Vongpatanasin et al. (23) found that estrogen administered orally increases circulating CRP levels twofold, whereas estrogen administered transdermally had no effect on circulating CRP levels. Similarly, patients taking oral HRT containing estrogens combined with progestogens had an increment in circulating CRP levels in the starting time 12 months of therapy compared to those using transdermal therapy who demonstrated no change in circulating CRP levels (22). In contrast, several other studies have instead shown that circulating CRP levels are reduced in humans treated with transdermal estrogen (24, 25). A reduction in CRP levels following peripheral estrogen administration supports the findings of Ashcroft et al. (26) demonstrating that estrogen reduces the inflammatory response during wound healing. The upshot of transdermal administration of estrogen on local CRP levels in peripheral tissues such as peel has not yet been elucidated, with previous studies measuring only circulating levels of CRP.
Isoforms of CRP
The pentameric protein, termed native CRP (nCRP), is characterized by a discoid configuration of five identical non-covalently bound subunits, each 206 amino acids long with a molecular mass of most 23 kDa. These 5 subunits lie in the same orientation effectually a central pore and arranged in a characteristic "lectin fold" with a two-layered beta canvass (15). Each subunit lies with the PCh binding site facing the "recognition" face up of the nCRP molecule (27). The molecule has a ligand-binding face up that has a characteristic feature of having two calcium ions per protomer. The calcium ions are of import for the stability and binding of ligands. The "contrary" face interacts with the C1q aspect of the complement pathway as well equally interacting with Fc receptors (6).
The pentameric poly peptide is synthesized primarily in liver hepatocytes but has also been reported to be synthesized in other jail cell types such as smooth muscle cells (28), macrophages (29), endothelial cells (30), lymphocytes, and adipocytes (31). CRP is first synthesized as monomers and and so assembled into the pentamer in the endoplasmic reticulum of the source cell. In hepatocytes, the pentameric poly peptide is retained in the endoplasmic reticulum past binding to two carboxylesterases, gp60a and gp50b (32). While in a resting (not-inflammatory) state, CRP is released slowly from the endoplasmic reticulum, but following an increment in inflammatory cytokine levels, the binding CRP to the carboxylesterases decreases and CRP is secreted rapidly (6). The stimulation of CRP synthesis mainly occurs in response to pro-inflammatory cytokines, most notably IL-six and to a lesser degree IL-1 and tumor necrosis alpha (TNF-α) (33).
Pentameric CRP can be irreversibly dissociated, with the resultant gratuitous subunits termed monomeric (or modified) CRP (mCRP). The dissociation of nCRP into free subunits has been observed at either high concentrations of urea (34) or high temperatures in the absence of calcium (35). The mCRP molecules are distinguished from nCRP by their different antigenic, biological, and electrophoretic activities (36) and by the fact that they express different neoepitopes (37). The ii isoforms of CRP have been shown to take distinct biological functions in the inflammatory process. For example, Khreiss et al. (37) provided bear witness that nCRP suppresses the adherence of platelets to neutrophils, whereas mCRP enhances these interactions. This deviation in part can be explained by the two isoforms binding to differing types of Fcgamma (Fcγ)-receptor involved in the signaling process. The mCRP isoform utilizes the low-affinity immune complex bounden immunoglobulin G (IgG) receptor chosen FcγRIIIb (CD16b) on neutrophils and FcγRIIIa (CD16a) on monocytes, while nCRP binds to the depression-affinity IgG receptor FcγRIIa (CD32) (38).
Bear witness is emerging of new structural intermediates of CRP with biological office. Ji et al. (39) found that the native protein first dissociates into subunits while retaining some of the native conformation before fully dissociating into mCRP. This intermediate, termed mCRPgrand, is formed when the nCRP is leap to cell membranes and and so dissociates, assuasive the subunits to retain some of the conformation before fully dissociating into mCRP subunits on disengagement from the membrane. It is suggested that this transitional process allows for more effective regulation of CRP function, with mCRPm allowing for the enhanced activation of the classical complement pathway (39). Further piece of work needs to exist conducted to determine the biological functions of the mCRPm intermediate, but initial findings suggest that information technology behaves in a like style to mCRP, typically promoting pro-inflammatory activeness.
CRP in Illness Pathology
The majority of CRP research has focused on the part of CRP and its isoforms on cardiovascular disease and stroke. CRP is used as a clinical marker of inflammation, with elevated serum levels beingness a strong independent predictor of cardiovascular illness in asymptomatic individuals (xl). CRP levels accept been linked to prognosis in patients with atherosclerotic disease, congestive centre failure, atrial fibrillation, myocarditis, aortic valve disease, and heart transplantation, suggesting that information technology has an agile part in the pathophysiology of cardiovascular disease (41). High-sensitivity assays, such every bit nephelometric assays, are used to detect baseline levels of CRP and patients who are at gamble of cardiovascular illness. An private with a CRP level college than 3 mg/L has an increased risk of coronary heart disease (42), and this risk increases in those with type ii diabetes (43).
Increased levels of CRP take been plant in patients with appendicitis, cholecystitis, pancreatitis, and meningitis (44). In patients suffering possible symptoms of appendicitis, acute appendicitis can be excluded in those with CRP levels lower than 25 mg/L in blood taken 12 h later on the onset of symptoms (45). When clinical symptoms of cholecystitis occur concurrently with CRP levels of over 30 mg/L, an accurate diagnosis of cholecystitis can be obtained with 78% sensitivity, suggesting that CRP is a more sensitive marking than erythrocyte sedimentation rate and white jail cell count in supporting cholecystitis diagnosis (46). In terms of acute pancreatitis, CRP levels of more 210 mg/50 were able to discriminate between mild and severe cases, with 83% sensitivity and 85% specificity (47). Serum CRP is elevated in bacterial meningitis, and resolution of symptoms following treatment with antibiotics is deadening in those with the highest CRP levels (48). Measurement of CRP in cerebrospinal fluid has a sensitivity of 100% and a specificity of 94% for differentiating between patients with bacterial meningitis, viral meningitis, and no infection (49).
Although studies accept shown that CRP levels increase during infections and inflammatory diseases, the precise role of CRP isoforms in their evolution and progression remains largely unknown. Thus, urgent investigations are required to determine the effects of each CRP isoform on specific cellular processes during affliction development. Evidence shows that in general nCRP tends to exhibit more anti-inflammatory activities relative to the mCRP isoform, possibly because nCRP limits the generation of the membrane assail complex (MAC) and C5a, thus inhibiting the alternative complement activation (50). In contrast, mCRP can accept marked pro-inflammatory backdrop both in vitro and in vivo by promoting monocyte chemotaxis and the recruitment of circulating leukocytes to areas of inflammation via Fcy-RI and Fcy-RIIa signaling (l). Thus, in addition to therapeutic strategies to inhibit CRP activity (51), more than targeted therapies accept been proposed for the handling of CRP-mediated pathologies, including inhibiting mCRP action (52) or preventing the dissociation of nCRP into mCRP (53).
CRP and Inflammation
C-reactive poly peptide levels are known to increase dramatically in response to injury, infection, and inflammation (Effigy 1). CRP is mainly classed equally an astute marker of inflammation, merely research is starting to indicate important roles that CRP plays in inflammation. CRP is the principal downstream mediator of the acute-stage response post-obit an inflammatory result and is primarily synthesized by IL-6-dependent hepatic biosynthesis (54, 55). The main role of CRP in inflammation tends to focus around the activation of the C1q molecule in the complement pathway leading to the opsonization of pathogens. Although CRP can initiate the fluid phase pathways of the host defense by activating the complement pathway, it tin can also initiate cell-mediated pathways by activating complement as well as to bounden to Fc receptors of IgG (54). CRP binds to Fc receptors with the resulting interaction leading to the release of pro-inflammatory cytokines (56). CRP besides has the power to recognize cocky and foreign molecules based on the blueprint recognition, something that other activators of complement such equally IgG cannot achieve because these molecules only recognize distinct antigenic epitopes (56).
Summary of studies investigating the role of native C-reactive protein (CRP) and monomeric CRP in inflammation, infection, and disease.
Evidence suggests that CRP is not just only a marker of inflammation simply also plays an active role in the inflammatory process. However, most early research in the literature simply refers to CRP and does not distinguish betwixt the two isoforms. Thus, unlike more than recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was oft not specified which CRP isoform was measured or utilized in experiments, whether responses attributed to nCRP were in fact possibly due to fractional/full dissociation into mCRP or if lipopolysaccharide (LPS) contamination could be present. More recent studies generally distinguish betwixt the differential furnishings of each CRP isoform on inflammatory processes, simply since antibodies for mCRP are not commercially available to date, few laboratories are able to behave studies investigating the mCRP isoform.
There is increasing evidence that CRP has a functional role in the inflammatory process. It is well established that CRP is an astute marker of inflammation and that its concentration increases in circulation during inflammatory events. CRP is deposited at sites of inflammation and tissue harm in both naturally occurring and experimental conditions (57). However, there is a raft of published data investigating CRP that does non consider its ii different isoforms. Understandably, when some of these studies were conducted, the existence of two CRP isoforms was not well established and available antibodies would have been raised against the pentameric nCRP alone. Another issue with published data is that CRP localization is often investigated in only a narrow range of inflammatory weather and tissue types. Although the mCRP isoform has been shown to be insoluble in plasma, it becomes localized in inflamed tissues and amplifies a pro-inflammatory response by a positive feedback loop (58).
The literature suggests that CRP binds to damaged jail cell membranes and contributes to the inflammatory response (59), with CRP molecules becoming associated with last complement complexes, specially in atherosclerotic lesions (lx). Lagrand et al. (61) provided evidence that CRP localizes to infarcted heart tissue and promotes local complement activation, triggering further damage to the heart tissue. Gitlin et al. (62) concluded that CRP was localized to the nuclei of cells within the synovium of rheumatoid arthritis patients, but the cell blazon was not identified at the time. All the same, other studies betoken no meaning localization of CRP in a number of pathologies, suggesting that CRP is found predominantly in the fluid stage rather than condign deposited in tissues at sites of inflammation or injury (63). There has been little enquiry conducted on the localization of CRP in inflammatory cells to appointment. At that place is a correlation between the localization of CRP in neutrophil infiltrates, especially in lesions of vasculitis and allergic encephalomyelitis (64, 65).
CRP and Infection
C-reactive protein is a marker for inflammation, and its levels increment during bacterial infection (66). Kingsley and Jones (67) stated that CRP increases during infection in response to monocytic mediators such every bit IL-1 and IL-6 and that it has a stable decay rate. It is thought that most of the interaction between CRP and the allowed response to pathogens involves the bounden of CRP to PCh and the activation of the classical complement pathway (68). Mold et al. (69) showed that CRP provides mice with protection against infection by the gram-positive pathogen Streptococcus pneumoniae by binding to a PCh determinant of the pathogen jail cell wall and activating the complement pathway. Mice pretreated with 200 µg CRP before being infected showed an increase in pct survival beyond all pathogen doses tested. The study ended that the power of CRP to protect against infection lies in its ability to demark to pneumococcal polysaccharide C in the bacterial cell wall (69).
Szalai et al. (70) showed that CRP can confer protective benefits against Salmonella enterica serovar Typhimurium, a gram-negative pathogen that provides a model of typhoid fever in mice. By using transgenic mice expressing human CRP, the written report found that CRP offered protection against a depression dose of Typhimurium and increased resistance to a fatal infection with a low dose of Typhimurium. Szalai et al. (lxx) concluded that CRP increases the early clearance of intravenously injected bacteria from the blood and reduces dissemination of bacteria to the liver and spleen during the initial stages of infection, thus allowing the mice to survive infection.
Marnell et al. (71) reviewed the protective role CRP against Haemophilus flu infection in both transgenic and wild-type mice treated by passive inoculation. CRP was shown to bind the pneumococcal C-polysaccharide of bacteria and opsonize them for phagocytosis. This procedure did non require the use of the Fcγ receptors, suggesting that CRP is not primarily protective by direct opsonization simply more likely through activation of complement and subsequent opsonophagocytosis.
Kingsley and Jones (67) tested whether CRP could be used to distinguish unlike types of infections. They discovered that mean CRP levels in a spreading infection were higher than those in other colonized, critically colonized, and locally infected groups. All cases of infection showed an increase in CRP levels compared to not-infected controls, but CRP levels could not distinguish between the infection types, showing that information technology is infection in general that causes CRP levels to increment, rather than the type of infection. This was as well noted by Healy and Freedman (66) who showed that CRP levels can be used only equally a method of detecting infection, rather than distinguishing information technology.
C-reactive protein tin mediate host responses to Staphylococcus aureus including some protective function against infection and an increase in phagocytosis of this pathogen. Povoa et al. (72) stated that the normal CRP level for the good for you population is about 0.08 mg/dL, and this increases to more than viii.7 mg/dL during chronic Due south. aureus infection. Thus, CRP can be used every bit an indicator of infection, alongside a body temperature of more than 38.2°C. Patterson and Mora (73) observed that enhanced resistance to intraarticular infection with Due south. aureus in chickens was associated with an increase in serum CRP and that isolated preparations of the protein produced antibacterial activity. Mulholland and Cluff (74) discovered that endotoxin-induced changes in resistance to local infection with Southward. aureus in rabbits were correlated with the circulating levels of leukocytes in the blood. The study showed that induced resistance was paralleled past an increase in CRP and leukocytes. This was collaborated by Patterson et al. (75) who found an clan between CRP and not-specific resistance to infection, including Southward. aureus and showed that CRP was acting upon the polysaccharide bacterial cell wall. Black et al. (three) stated that CRP enhances the in vitro phagocytosis of many microorganisms (including Southward. aureus) by leukocytes. Their piece of work confirmed this finding even in the absenteeism of complement, suggesting that the enhancement of phagocytosis by CRP is due to the interactions with Fcγ receptors.
In summary, prove shows that CRP is not only a mark of infection and inflammation but that CRP also has a protective role against bacterial infections (Figure 1), principally through the activation of complement and subsequent opsonization of pathogens.
CRP and Complement
Complement is one of the major defenses of the homo immune system that is involved in the clearance of foreign particles and organisms after recognition by antibiotic. The complement pathway is made upwardly of 35 plasma or membrane proteins that is an important organization in immunity and the defense of the host against microbial infection. The components of the complement pathway tin can exist activated in three different pathways to trigger a cascade of proteins, which are used to help demark microbial surfaces for the immune system to recognize and activate phagocytosis (76, 77). The classical pathway is triggered by a target leap antibody, whereas the lectin pathway is triggered by microbial repetitive polysaccharide structures and the culling pathway is triggered by recognition of other foreign surface structures. Even though the triggers are different, the three pathways merge at a pivotal activation of the C3 and C5 convertases. A majority of the components are synthesized in the liver, C1 in the intestinal epithelium, and gene D in the adipose tissue (76).
The role of CRP in activating the complement pathway has been extensively investigated. In 1974, Kaplan and Volanakis start described the power of CRP to activate the classical complement pathway using C-polysaccharide and phospholipid ligands (59). The activation of complement by CRP is considered a crucial step since when complement was depleted, and the furnishings of CRP were abrogated (fifty).
The opposite face of the CRP molecule, which is typically complexed with polyvalent ligand or chemically cross-linked, binds to C1q and activates the classical complement pathway (56). C1q is a big 460-kDa molecule made up of six identical subunits, each fabricated up of three structurally similar but singled-out polypeptide chains (78). This process requires the use of calcium ions for the stable formation of the C1 complex (79). CRP is most constructive during the early classical pathway activation of C1, C4, and C2 (80). This is considering the ligand-bound interaction with C1q leads to the formation of C3 convertase, triggering the complement activation of C1–C4 simply with little activation of the late complement proteins C5–C9 (fifteen).
Activation of complement past CRP varies from activation by antibiotic in that CRP has selective activation of early on components without the need to class the MAC. In addition to activating the classical complement pathway, CRP can inhibit the alternative complement pathway by decreasing C3 and C5 convertase activities and inhibiting the complement amplification loop. This is achieved by the recruitment of factor H to the cell surface and by preventing C5 convertase cleaving C5 to recruit neutrophils and prevent the formation of the MAC (71). As the levels of CRP increment, this causes decreased bounden of C3b and C5b-9 to liposomes, perhaps besides explaining the lack of C5–C9 consumption by CRP during classical pathway activation (80).
Both the initiator (C1q) and the inhibitor (C4bp) of the archetype complement pathway compete for mCRP binding, with the competition controlling the local rest of activation and inhibition of the pathway in tissues (58). Interestingly, mCRP but non nCRP binds the C4bp inhibitor, suggesting that mCRP rather than nCRP is able to provide a loftier degree of control over the archetype complement pathway (58).
CRP and Apoptosis
There has been little inquiry conducted into the effect of CRP on the proliferation process. However, at that place is evidence that CRP has a major role in the apoptosis process. Devaraj et al. (81) showed that CRP stimulates the product of pro-apoptotic cytokines and inflammatory mediators via the activation of Fc-γ receptors. The pro-apoptotic cytokines and inflammatory mediators induced by CRP include interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), and reactive oxygen species (82, 83).
C-reactive poly peptide induces the upregulation of p53 in monocytes and affects jail cell cycle kinetics of monocytes through CD32 (FcγRII), inducing apoptosis past G2/M arrest in the cell cycle (84). CD32 receptors have been shown to trigger apoptotic signals and are expressed in a subset of monocytes that polarize to pro-inflammatory macrophages, suggesting that CRP may dampen macrophage-driven pro-inflammatory responses by inducing apoptosis (85).
C-reactive poly peptide is elevated in cardiovascular disorders and is a mediator of atherosclerosis. CRP localizes directly in the atherosclerotic plaques where it induces the expression of genes that are straight involved in the adhesion of monocytes and the recruitment of intracellular molecules such as Due east-selectin and monocyte chemoattractant protein-1 (MCP-i). CRP has likewise been shown to play a function in mediating low-density lipoprotein uptake in macrophages and activating the complement arrangement, which is implicated in atherogenesis (86). Apoptosis occurs in atherosclerotic plaques and the number of apoptotic cells increment equally lesions become more advanced. As cells become apoptotic, they start to cause plaque disruption, leading to the expression of growth arrest- and DNA damage-inducible cistron 153 (GADD153). GADD153 upregulation has been shown to induce Yard1 abort or apoptosis in some cancer cell lines (87). Blaschke et al. (88) institute that CRP can induce the apoptosis of man coronary vascular smoothen muscle cells through a caspase-mediated machinery, specially through increased caspase-3 activeness. CRP was co-localized to the GADD153 gene product in atherosclerotic lesions suggesting that CRP is triggering the caspase cascade and apoptosis past inducing the expression of the GADD153 gene.
There is footling research on how the two isoforms of CRP interact with the apoptosis procedure. It is suggested that CRP can exert anti-apoptotic activity but only when the cyclic pentameric structure is lost. This would suggest that the apoptotic activity of CRP is induced through the native isoform. Native CRP (nCRP) tin can bind to low-affinity IgG FcγRIIa (CD32) and IgG FcγRI (CD64), leading to depressed functional activities, degranulation, and the generation of superoxide past inducible respiratory outburst. On the other manus, mCRP binds to low-affinity IgG FcγRIIIb (CD16) that can filibuster apoptosis by triggering the cell survival pathway in neutrophils, fifty-fifty at low concentrations (89).
The nCRP isoform has the ability to opsonize apoptotic cells and induce the phagocytosis of damaged cells. Removal of nCRP-bound apoptotic monocytes and macrophages may be via FcγR-mediated phagocytosis (84). CRP binds to apoptotic cells, inhibits the assembly of terminal complement components, and promotes the opsonization of apoptotic cells (89, ninety).
CRP and Nitric Oxide (NO)
C-reactive protein has the ability to benumb NO product with a marked reduction in in vitro angiogenesis, cell migration, and capillary-like tube germination by CRP at concentrations known to cause cardiovascular risk (91). Eisenhardt et al. (15) showed that CRP upregulated the expression of adhesion molecules and inhibited endothelial nitric oxide synthase (eNOS) expression, indicating a role for CRP in the production of NO. Several studies have revealed that CRP inhibits NO production via downregulation of eNOS in cardiovascular endothelial cells, thereby inhibiting angiogenesis in vitro and promoting the pathogenesis of atherosclerotic vascular illness through vasoconstriction, leukocyte adherence, and inflammation (14, 91–93). Another study plant that it was in fact the nCRP isoform that downregulated eNOS and thus impaired endothelial function in ApoE knockout mice, via a mechanism idea to involve iNOS (94). Eisenhardt et al. (15) provided prove that nCRP suppresses endothelium-dependent NO-mediated dilation by activating the p38 mitogen-activated poly peptide kinase (MAP kinase) pathway and NADPH oxidase, suggesting that multiple pathways could be interacting with this procedure.
In contrast, mCRP has the opposite outcome, enhancing NO production in neutrophils via upregulation of eNOS (95) with reverse transcription polymerase chain reaction showing an distension of eNOS mRNA, just not iNOS or nNOS mRNA. This written report highlighted that mCRP initiates calcium (Ca2+) mobilization and activation of calmodulin and PI3 kinase to induce NO formation in neutrophils (95). The effect of CRP isoforms on other inflammatory cells, such as monocytes or macrophages, has not been investigated to date.
CRP Isoforms and Inflammatory Cytokines
There has been increasing show of a relationship between CRP and several pro-inflammatory cytokines.
IL-vi and CRP
Interleukin-six is a pro-inflammatory cytokine secreted by various cells including inflammatory cells, keratinocytes, fibroblasts, and endothelial cells. Information technology regulates the acute-stage response, and its main part involves the host response to infection (96). Even though information technology is predominantly a pro-inflammatory cytokine, in some cells, IL-6 tin accept regenerative and anti-inflammatory effects through the activation of membrane-bound IL-six receptor signaling (97).
Interleukin-six is synthesized in the initial stages of inflammation and induces a number of astute-phase proteins, including CRP (98). IL-half dozen can also reduce the production of fibronectin, albumin, and transferrin as well as the promotion of CD4+ T helper cells, which initiates the linking of innate and acquired immunity (98). At that place is a correlation between increasing levels of IL-six during inflammation and increasing levels of CRP (11), with IL-half dozen inducing the CRP factor (12). Nonetheless, well-nigh investigations of CRP production past IL-half dozen mostly fail to indicate which isoforms of CRP are generated. In some cases, the antibodies used suggest that nCRP is present, but given IL-6 occurs at the sites of inflammation, the pentameric CRP may exist dissociating into mCRP.
When CRP levels become elevated in atheroma, this leads to the induction of IL-6 by macrophages indicating that CRP may accept a straight effect on IL-6 release (99). Krayem et al. (100) institute that a combination of mCRP, nCRP, and oxLDL decreases IL-six production in a model of atherosclerosis. This triple combination suggests that nCRP might downregulate the IL-6 release by macrophages that have been stimulated by both mCRP and oxLDL.
Interleukin-8 (IL-8) and CRP
Interleukin-eight is a cytokine produced past numerous cell types including inflammatory cells, keratinocytes, fibroblasts, and endothelial cells. IL-8 acts as a strong chemoattractant of neutrophils (101) and is overexpressed in chronic inflammatory diseases and during septic daze (102). IL-8 stimulates the release of granules from neutrophils by a procedure called degranulation. These granules comprise a range of antimicrobial effectors that tin can assistance combat infection (103). Neutrophils are the commencement inflammatory cells to arrive at the site of inflammation, and they behave out the phagocytosis of leaner and release chemotactic mediators that recruit other leukocytes to the affected tissue (103).
Kibayashi et al. (104) indicated that CRP plays a function in atherosclerosis via enhanced IL-eight product and increased expression of IL-8 mRNA in a CRP dose-dependent mode. They showed that CRP promotes IL-8 production via the activation of the ERK, p38 MAPK, and JNK pathways. Conversely, Wigmore et al. (105) indicated that IL-eight induces CRP production in hepatocytes, providing a potential feedback loop. The upshot of the unlike CRP isoforms on IL-8 production has been investigated. Khreiss et al. (37) showed that nCRP had no detectable effect on the production of IL-eight, whereas mCRP increased IL-viii product and IL-8 gene expression, promoting pro-inflammatory activity through a p38 MAPK-dependent mechanism. When treated with anti-CD16, there was inhibition of mCRP-stimulated NO germination and IL-8 release.
MCP-ane and CRP
Monocyte chemoattractant protein-1 is a cytokine that plays a function in the regulation of migration and infiltration of monocytes and macrophages (106). It is released by a number of cell types in response to events such as oxidative stress, cytokine release, and growth gene release (107). Human MCP-1 is known to bind to at least two receptors, and its production can be induced by interleukin-4 (IL-iv), IL-1, TNF-α, bacterial LPS, and IFN-γ (107). There is increasing evidence that MCP-1 influences T-prison cell immunity by enhancing the secretion of IL-four by T cells, as well as having a role in the migration of leukocytes (106). This in plough has a regulatory role on monocytes and macrophages, which are the major source of MCP-1 (107). MCP-1 is known to recruit monocytes to the vessel wall (99) and cause the arrest of rolling monocytes on endothelial monolayers that express E-selectin (108).
Evidence suggests that CRP stimulates endothelial cells to express MCP-ane (99) in addition to beingness a directly chemoattractant of monocytes itself (109). CRP can promote monocyte chemotactic activity in response to MCP-ane via upregulation of the monocyte chemotaxis receptor CCR2, with elevated CRP levels promoting the aggregating of monocytes in the atherogenic arterial wall (99). When vascular smooth muscle cells are exposed to increasing levels of CRP, MCP-one mRNA essentially increased inside two h and remained elevated for at least 24 h (110). Incubation with mCRP increases the secretion of MCP-1, leading to pro-inflammatory action through a p38 MAPK-dependent mechanism, whereas nCRP had no detectable event (37).
TNF-α and CRP
Tumor necrosis factor-α is a component of the acute-phase response and is mainly produced by monocytes and macrophages but can be produced by numerous other immune cells such as neutrophils, natural killer cells, and eosinophils. TNF-α is non usually detectable in a salubrious host, but levels go elevated in a number of inflammatory and infectious conditions (111). The primary stimulant of TNF-α product is LPS, simply many other pathological weather such every bit trauma infection, impaired wound healing, and eye failure also induce its production (111, 112). TNF-α mediates various processes such as cell proliferation, differentiation, and apoptosis.
Studies take shown a correlation betwixt TNF-α production and the concentration of CRP. TNF-α induces a dose-dependent secretion of CRP in hepatocytes, which corresponds to an increment in CRP mRNA (28). Conversely, elevated CRP levels in atheroma leads to the consecration of IL-1β, IL-6, and TNF-α production past macrophages (99). Inquiry shows a close relationship between TNF-α and IL-half dozen levels in inflammation (113), with both TNF-α and IL-six inducing the transcription of CRP (33). All the same, there is some contradictory evidence showing a potential inhibitory effect of CRP on TNF-α product, suggesting that in that location could be a negative feedback machinery whereby elevated levels of CRP inhibit further stimulation of CRP by reducing the TNF-α production (114). A combination of mCRP, nCRP, and oxLDL as well causes a decrease in both TNF-α and IL-6 product in a macrophage model of atherosclerosis (100). This triple combination suggests that nCRP might downregulate TNF-α and IL-6 product by macrophages stimulated past both mCRP and oxLDL.
Determination
C-reactive poly peptide is a homopentameric astute-phase inflammatory poly peptide that exhibits elevated expression during inflammatory conditions such as rheumatoid arthritis, some cardiovascular diseases, and infection. Evidence suggests that CRP is an of import regulator of inflammatory processes and not just a marker of inflammation or infection. Cardinal areas of inflammation and host responses to infection mediated by CRP include the complement pathway, apoptosis, phagocytosis, NO release, and cytokine production. Nevertheless, near research to date has investigated the role of CRP in the vascular tissues, highlighting the need to conduct further work to make up one's mind the precise role of CRP in peripheral tissues.
C-reactive poly peptide is synthesized primarily in liver hepatocytes just likewise other cell types such as smoothen muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Evidence as well suggests that the sex steroid hormone estrogen can influence CRP levels, with HRT having a profound influence on CRP levels in the elderly. Administration of oral HRT increases background levels of CRP in circulation, whereas bear witness suggests that transdermal estrogen supplementation either reduces or has fiddling effect on circulating CRP levels. A reduction in CRP levels following local assistants of estrogen supports findings showing that estrogen reduces the inflammatory response in peripheral tissues such as peel.
There are ii distinct isoforms of CRP, nCRP and mCRP, and the nCRP isoform can irreversibly dissociate at sites of inflammation, tissue impairment, and infection into 5 mCRP subunits. Evidence indicates that nCRP often tends to showroom more than anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis, and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and tin can delay apoptosis. The nCRP and mCRP isoforms inhibit and induce NO product via downregulation and upregulation of eNOS, respectively. In terms of pro-inflammatory cytokine product, mCRP increases IL-8 and MCP-ane production, whereas nCRP has no detectable result on their levels. CRP can also induce IL-vi and TNF-α production at sites of inflammation, once more suggesting probable involvement of mCRP from the dissociation of nCRP. Further studies are needed to aggrandize on these emerging findings and to fully characterize the differential roles that each CRP isoform play at sites of local inflammation and infection.
Author Contributions
Both authors contributed equally to the planning, preparation, drafting and writing of the article.
Conflict of Interest Statement
The authors declare that the enquiry was conducted in the absence of any commercial or financial relationships that could be construed equally a potential conflict of interest. The handling Editor declared a shared affiliation, though no other collaboration, with the authors.
Footnotes
Funding. This work was funded by Manchester Metropolitan University.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908901/
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