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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Adv Exp Med Biol. Author manuscript; available in PMC Jun 5, 2012.
Published in final edited form as:
Adv Exp Med Biol. 2009; 653: 98–116.
PMCID: PMC3367411
NIHMSID: NIHMS380448

Pattern Recognition by Pentraxins

Abstract

Pentraxins are a family of evolutionarily conserved pattern-recognition proteins that are made up of five identical subunits. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver while PTX3 is produced in a variety of tissues during inflammation. The main functions of short pentraxins are to recognize a variety of pathogenic agents and then to either eliminate them or neutralize their harmful effects by utilizing the complement pathways and macrophages in the host. CRP binds to modified low-density lipoproteins, bacterial polysaccharides, apoptotic cells, and nuclear materials. By virtue of these recognition functions, CRP participates in the resolution of cardiovascular, infectious, and autoimmune diseases. SAP recognizes carbohydrates, nuclear substances, and amyloid fibrils and thus participates in the resolution of infectious diseases, autoimmunity, and amyloidosis. PTX3 interacts with several ligands, including growth factors, extracellular matrix component and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes. In addition, data in gene-targeted mice show that PTX3 is essential in female fertility, participating in the assembly of the cumulus oophorus extra-cellular matrix. PTX3 is therefore a nonredundant component of the humoral arm of innate immunity as well as a tuner of inflammation. Thus, in conjunction with the other components of innate immunity, the pentraxins use their pattern-recognition property for the benefit of the host.

Pentraxins

Pentraxins are a family of phylogenetically conserved, pattern-recognition proteins and a host-defense-related component of the innate immune system.15 Based on the length of their primary structure, the pentraxins are divided into two groups: short pentraxins and long pentraxins. Short pentraxins include C-reactive protein (CRP) and serum amyloid P component (SAP). The first discovered long pentraxin, known as pentraxin 3 (PTX3), serves as the prototype protein of the long pentraxin group. The term pentraxin was first assigned to CRP for its pentagonal appearance of five subunits in electron micrographs.6 Pentraxins (Table 1) recognize a wide range of altered-self and nonself pathogenic substances and lead to protection of the host.

Table 1
The pattern-recognition property of pentraxins involved in host-defense

Short Pentraxins: CRP and SAP

CRP, the most characteristic acute phase protein in humans, was discovered in 1929.7 The plasma concentration of CRP rises in both chronic and acute inflammatory conditions.7,8 SAP was discovered in 1965 as an amyloid protein of plasma (P) origin and is not an acute phase protein in humans.9 SAP is associated with the deposits that characterize amyloid fibrils in systemic amyloidosis, Alzheimer’s disease and the transmissible spongiform encephalitis.10 In mouse, which is a widely used animal to determine the in vivo functions of short pentraxins, SAP is the acute phase protein.11 CRP is only a trace serum protein in mice and not an acute phase protein.

Phylogeny

Both CRP and SAP have been found in all vertebrates where they have been sought.12,13 CRP is also found in the hemolymph of invertebrates such as the arthropod Limulus polyphemus and the mollusc Achatina fulica.14,15 At least one short pentraxin is present in all vertebrates as well as in some invertebrates. Humans have got both CRP and SAP. The pattern-recognition property of the short pentraxins towards a wide range of substances of biological importance has been conserved throughout evolution although their acute phase nature is species-specific. For example, in contrast to humans and mice, in rats CRP is constitutively expressed at relatively high levels and is only a minor acute phase protein.16

Metabolism

The major site of CRP synthesis is liver.17 In vitro, in human hepatoma cells, cytokines IL-6 and IL-1 are the main inducers of CRP expression.1820 Nitric oxide has been shown to reduce the induction of CRP production by cytokines.21 Expression of CRP mRNA in the tissues other than the liver has also been reported.22,23 In mice transgenic for human CRP, the CRP gene has been shown to be under hormonal control while in hamsters, SAP gene is under hormonal control.24,25 In healthy persons, the median concentration of CRP is 0.8 mg/L but, following an acute-phase stimulus, this may increase to more than 500 mg/L. The half-life of CRP is about 19 h in humans.26 SAP is also produced exclusively by hepatocytes and turnover rapidly with plasma half-life of 24 h.27 SAP and CRP are both resistant to proteolysis. SAP, which has localized to the deposits, persists there for prolonged periods without being catabolized.10

Structure

CRP has five identical, 206 amino acid long subunits of 23 kD each.28,29 A single internal disulfide bond is present in each subunit.29 There is no carbohydrate present in human CRP and there are no potential N-glycosylation sites either. The subunits are held together through noncovalent interactions and are arranged in pentameric symmetry.30 Each subunit is made up of two antiparallel β-sheets and a single short α-helix, and is characterized by the presence of a cleft that extends from about the center of the subunit to its edge at the central pore of the pentamer. The overall dimensions of the CRP pentamer are about 102 Å outside diameter with a central pore diameter of 30 Å and a subunit diameter of 36 Å.30 SAP, on the other hand, is a glycoprotein made up of five noncovalently attached subunits of 23 kd each.31,32 SAP is a single pentamer in serum but under certain conditions, SAP forms decamers by stacking of two pentamers.33 The complete glycoprotein structure is important for the functions of SAP.10

Binding to Calcium and Phosphocholine

CRP is called so because it reacts with C-polysaccharide of the cell wall of Streptococcus pneumoniae.7 The reaction of CRP and C-polysaccharide requires calcium ions.34 CRP binds two Ca2+ through the two overlapping Ca2+-binding sites present on each subunit.30 The two Ca2+ in CRP are coordinated by Asp60, Asn61, and by residues (Glu138, Gln139, Asp140, Glu147 and Gln150) in a loop. This loop, in the absence of bound Ca2+, moves away from the main body of the CRP molecule exposing an otherwise hidden site of proteolysis. Bound Ca2+ are integral structural elements of CRP and protect CRP from proteolytic cleavage.35

Phosphocholine (PCh) is the principal Ca2+-dependent ligand of CRP.36 The PCh-containing substances, to which CRP binds, are present in many prokaryotes and in all eukaryotes and include pneumococcal C-polysaccharide, damaged, necrotic and apoptotic cells, altered lipid bilayers, and pulmonary surfactant lipids.24,37 CRP also binds in a Ca2+-dependent manner to phosphoethanolamine and other phosphate monoesters.24 A PCh-binding site, located next to the Ca++-binding sites, is present on each CRP subunit. Since the subunits have same orientation in the assembled pentamer, all five PCh-binding sites fall on the same face of the CRP pentamer. The PCh-binding site consists of a critical hydrophobic pocket formed by residues Leu64, Phe66 and Thr76, and two Ca2+ that are bound to CRP.38 The phosphate group of PCh directly coordinates with the two Ca2+. Phe66 and Glu81 in CRP provide contacts to the choline moiety of PCh that lies within the hydrophobic pocket.3841

Like CRP, SAP also binds two Ca2+ through the two overlapping Ca2+-binding sites present on each subunit.32 Ca2+-bound SAP is also protease-resistant.42 Since SAP binds to phosphoethanolamine, it can bind to necrotic and late apoptotic cells in Ca2+-dependent manner.43 SAP pentamers are also capable of interacting with CRP pentamers to form decamers but only in Ca2+-free conditions, indicating that CRP and SAP do not interact in vivo.44,45

Binding to Bacteria and Protective Role against Microbial Infections

CRP binds a wide variety of bacteria including several serotypes of S. pneumoniae, Haemophilus influenzae, and Neisseriae spp.4649 In vitro, CRP has been shown to promote phagocytosis of PCh-expressing bacteria and to block the attachment of such bacteria to the receptors for platelet-activating factor (PAF) on the host cells.48,50

Human CRP protects mice against fatal infection with S. pneumoniae.5153 Employing complement C3 knockout mice and complement depletion using cobra venom factor, it has been shown that a functioning complement system is required for full CRP-mediated protection.5153 However, the protection is independent of naturally occurring anti-pneumococcal antibody.54 CRP also protects mice from infection with Salmonella typhimurium, a pathogen to which CRP is not known to bind.55

SAP binds to several bacteria via lipopolysachharide (LPS) and prevents LPS-mediated complement activation.56 SAP binds LPS and thereby protects the host from LPS toxicity.57,58 However, for certain organisms to which SAP binds, such as S. pyrogens and rough strains of E. coli, SAP enhances virulence by protecting the bacteria against phagocytosis.59 SAP is not involved in resistance against TNFα-induced lethal hepatitis shock.60 SAP enhances the ability of mouse macrophages to kill Listeria monocytogenes and this activity is not associated with the binding of SAP to the pathogen.61 It has been shown that SAP is protective in infection with organisms to which it does not bind.59

Binding to Lipoproteins: Implications for Atherosclerosis

Another major CRP-ligand of tremendous biological significance is modified low-density lipoprotein (LDL). CRP readily gets complexed in a Ca2+-dependent manner to modified (oxidized and enzymatically-treated) LDL but not to native LDL.6265 Binding of CRP to LDL is mediated by the PCh-binding site in CRP that interacts with the PCh and cholesterol moieties present on LDL.64,65 Consistent with the interaction between CRP and LDL in vitro, CRP has been found deposited and colocalized with LDL in human atherosclerotic lesions.66,67 CRP is thus capable of covering certain properties of modified LDL such as complement activation. It has been shown that CRP protects the host from complement activation by LDL.68 However, CRP has not been found to be either atheroprotective or proatherogenic in mouse models of atherosclerosis.6971 Although the denatured CRP has been shown to be atheroprotective in mice, the role of intact CRP in the development of atherosclerosis is not clear.72

The serum level of CRP is raised in atherosclerosis. Measurement of serum CRP is recommended for use as an indicator of arterial inflammation and predictor of future cardiovascular events.73 Statins that lower cholesterol levels have also been shown to lower CRP levels.21 Recent data have indicated that the measurement of serum CRP levels alone, at least in individuals on statin-therapy, is not beneficial.

Binding to Nuclear Constituents: Role in Protection against Autoimmunity

The presence of CRP in the nuclei of synoviocytes and histiocytes in the patients with rheumatoid arthritis led to the finding that CRP binds nuclear materials such as chromatin, histones, small nuclear ribonucleoproteins, nuclear envelope proteins, and nucleosome core particles.7477 The interaction is Ca2+-dependent and involves the PCh-binding site of CRP.7577 CRP, however, does not bind chromatin in serum suggesting that this interaction occurs only if CRP or chromatin is deposited at sites of inflammation.78

SAP binds to histones and chromatin, and also to DNA. The binding is Ca2+-dependent and does not occur in serum.78,79 SAP binds chromatin in vivo also; it has been detected with the nuclear deposits in skin biopsies from lupus patients.80 CRP and SAP have a nuclear localization signal and thus their transport into nuclei is possible.81 The primary role of CRP and SAP is believed to be the disposal of nuclear materials released in the extracellular environment by apoptotic and necrotic cells, thereby preventing the hazard of autoimmunity.7779

In lupus-prone mice, CRP delays the onset of nephritis and increases clearance and prevents accumulation of immune complexes in the renal cortex. It also decreases autoantibody levels that reduces autoimmune manifestations and thus prolongs the survival.8284 Another important aspect of the role of short pentraxins in autoimmunity is their ability to bind immobilized IgG and immune complexes.85,86 SAP-deficient mice degrade chromatin more rapidly than normal, have enhanced antibody response to exogenous chromatin, and develop anti-chromatin autoimmunity and glomerulonephritis, a phenotype resembling lupus.87,88 Thus SAP, by controlling chromatin degradation, prevents glomerulonephritis although anti-nuclear antibodies are formed.

Binding to Polycations and Extracellular Matrix Proteins

For binding to certain ligands, CRP does not require Ca2+. Such ligands include polycations like protamine, leukocyte cationic proteins, and a variety of arginine-rich and lysine-rich cationic molecules, and extracellular matrix (ECM) proteins like fibronectin (Fn).8992 Instead, Ca2+ inhibits these interactions at the physiological pH. SAP also binds to Fn.93 The Ca2+-binding site of CRP participates in binding to Fn and polycations.92 On Fn, the C-terminal domain including the cell-binding and heparin-binding regions is involved in binding to CRP.91 The CRP-Fn interaction may explain in part the selective deposition of CRP at sites of tissue injury and may play a role in the formation of ECM needed for tissue repair.

No binding occurs between soluble CRP and Fn. The maximum interaction between CRP and Fn occurs at pH 5.0 and this interaction is not inhibited by Ca2+.90,92 Since CRP circulates in the blood in its Ca2+-bound form, it can interact with Fn exclusively at the ECM of the inflammatory sites including carcinomas where the pH goes down.90,92 Because CRP, Fn and the ECM have been implicated in cancer, it has been proposed that CRP-Fn interactions may change the architecture of ECM to modify the course of the disease progression.92 In mouse models of melanoma, CRP is tumoricidal and inhibits metastases.94

Binding to Carbohydrate Structures on the Parasite Surface

CRP also reacts with bacterial polysaccharides that do not contain PCh, with several galactans through galactose and phosphate residues, and to substances derived from fungi and yeast.85,9598 CRP also binds, in a Ca2+-dependent manner, to certain parasites such as Plasmodium falciparum, Hymenopepis diminuta, and Leishmania donovani through either PCh or carbohydrates on their surfaces.99102 Binding of CRP to L. donovani induces their developmental transformation.103 The PCh-binding site of CRP participates in binding of CRP to carbohydrate moieties.41

The carbohydrate-binding property of SAP is shown by the binding of SAP to agarose, microbial polysaccharides, aggregated IgG, Type IV collagen, calumenin, shiga toxin 2, lactate, influenza virus hemagglutinin, heparin, 6-phosphorylated mannose, 3-sulfated saccharides, and glycosaminoglycans.104108 Most of these interactions require Ca2+. The interaction of CRP and SAP with carbohydrates occur best at mildly acidic pH.85,109

The binding of SAP to glycosaminoglycans neutralizes its anticoagulant effect.110 Heparin, in the presence of SAP, is a better inhibitor of thrombin-catalyzed conversion of fibrinogen to fibrin than heparin alone, and thus SAP also inhibits fibrin polymerization.111 Heparin and lactic acid prevent SAP self-association, however, lactic acid does not dissociate SAP-heparin complex. Finally, SAP has been shown to enhance refolding of denatured lactate dehydrogenase and thus SAP also acts as a chaperone.112

Binding to Platelet-Activating Factor

CRP binds to PAF, -O-alkyl-sn-2-O-acetyl-n-glycero-3-phosphocholine, probably through the PCh group in PAF.113,114 CRP inhibits PAF-induced platelet-aggregation, inhibits binding of PAF to platelets, and prevents capture of neutrophils by platelets.115118 In vivo, CRP protects mice from lethal challenge with PAF.114,119 The platelets treated with CRP have been shown to kill immature form of Schistosoma mansoni in vitro and confer protection against S. mansoni in rats.120

Binding to Complement C1q and Modulation of the Classical Complement Pathway

Ligand-complexed CRP binds C1q, the first component of the classical pathway of complement, and activates the classical pathway of complement.121,122 CRP-initiated activation of complement leads to the assembly of an effective C3 convertase and generates anaphylotoxins C3a and C4a and the opsonins C4b, C3b, and iC3b. CRP-complexes do not result in the formation of an effective C5-convertase, and therefore prevent generation of pro-inflammatory molecules like C5a and also avoid the assembly of membrane-damaging, terminal membrane attack complex of the complement pathway.123

The C1q-binding site on CRP is located in the cleft regions present one on each subunit and is formed by Tyr175, Asp112, Glu88, His38, and Asn158. Residues Asp112 and Tyr175 appear to provide contacts with C1q.124,125 The CRP-binding site on C1q is located on the globular region of C1q.126128 SAP, in addition to binding to C1q, also binds to C4b-binding protein.129 Aggregated SAP and ligand-bound SAP activate the classical pathway of complement.130,131 The C1q-binding site on SAP is not known.

Complement activation by CRP-complexes participates in phagocytosis of apoptotic cells.132 CRP attenuates the formation of the membrane attack complex on the surfaces of apoptotic cells, thereby protecting the cells from lysis. This effect is achieved by the recruitment of factor H, a complement regulatory protein that accelerates the decay of the C3 and C5 convertases.132 The factor H-dependent inhibitory effect of CRP on activation of the alternative pathway of complement by S. pneumoniae and artificially sensitized erythrocytes has been observed.133135 Interestingly, the property of CRP to activate the classical pathway of complement is irrelevant for the protection of mice from pneumococcal infection.136

Binding to the IgG Receptors FcγRI and IIa and Interaction with Phagocytes

CRP interacts with phagocytic cells through the IgG receptors, FcγRI (CD64) and FcγRII (CD32), in heat-inactivated plasma, in cell culture medium, and in buffered solutions.137143 The exact physiological conditions in which this interaction can occur in vivo are unclear but it is reasonable to believe that either CRP should be ligand-complexed or the phagocytic cells should be immobilized. FcγRIIa, the low affinity IgG receptor providing stimulatory signals in the cells, is the high affinity receptor for CRP.139 In contrast, FcγRI, the high affinity IgG receptor providing inhibitory signals in the cells, is the low affinity receptor for CRP.138 The binding of CRP to FcγR is Ca2+-dependent, specific, saturable, reversible, and rapid with a half-life of 3 min.137143 PCh does not inhibit CRP-FcR interaction.142 Because IgG inhibits binding of CRP to FcγR, it is likely that the sites on FcγR that bind IgG and CRP are similar.141 A hydrophobic region present in the cleft on the CRP molecule provides the contact amino acids for FcγR. These amino acids are Thr173, Asn186, Lys114, and Leu176.144 Thus the binding sites on CRP for FcγR and for C1q are discrete but overlapping.

CRP affects the functions of the phagocytic cells such as augmentation of FcR-dependent aggregated IgG-mediated respiratory burst activity.145 Upon binding to monocytic cells, CRP is internalized and degraded.146 Although CRP enhances the phagocytosis of a variety of Gram-negative pathogens in vitro, it has been shown that the binding ability of CRP for FcγR is not required for protection of mice from pneumococcal infection.147 However, binding of CRP to FcγR is required for the protection of mice from LPS toxicity.148 CRP induces macrophage tumoricidal activity but it is not known whether CRP-FcγR interactions are involved.149 CRP also binds mouse FcγR.150152 SAP also binds to human and mouse FcγR.153,154

Binding of SAP to Amyloid Fibrils and Role in Amyloidosis

SAP binds to β-amyloid peptide in a Ca2+-dependent manner and inhibits the formation of amyloid fibrils.155,156 SAP has been shown to induce cell death in primary cultures of rat cerebral cortex suggesting that SAP may play a role in the development of Alzheimer’s disease.157 Binding of SAP to amyloid fibrils prevents proteolysis of the amyloid fibrils in vitro and thus enhances induction of amyloidosis in vivo as shown by delayed and reduced amyloid deposition in SAP-deficient mice.158,159 The interference with binding of SAP to amyloid fibrils in vivo may promote regression of the deposits.160 SAP-deficient mice do not necessarily develop severe autoimmune disease; they have high antinuclear antibodies but no glomerulonephritis.88

Long Pentraxin: PTX3

In the 1990s a new member of the pentraxin family was cloned in endothelial cells stimulated with IL-1 or in fibroblasts treated with TNFα.161,162 The prototypic long pentraxin 3 (PTX3) is characterized by a C-terminal domain sharing a high degree of homology with short pentraxins, associated to an unrelated long N-terminal domain. In spite of the sequence homology, PTX3 differs from CRP and SAP in terms of gene organization and chromosomal localization as well as cellular source, inducing-stimuli, and ligand-binding properties.1,163 PTX3 interacts with C1q, the growth factor FGF2, the ECM component TSG-6 and selected pathogens (Fig. 1).164169 Recent data in gene-targeted mice show that PTX3 has complex nonredundant functions in vivo, ranging from female fertility and innate immune response against diverse microorganisms, to the assembly of ECM.1,167,168,170173 PTX3 is highly conserved in evolution suggesting that the results obtained in animal models are likely to be informative for the function of PTX3 in humans. In humans, PTX3 plasma levels are very low in normal condition (≤2 ng/ml) but increase rapidly in several pathological conditions raising the possibility that PTX3 may have a diagnostic and prognostic role.

Figure 1
The long pentraxin PTX3 acts as a soluble multifunctional protein. The multifunctional properties of PTX3 involve interaction with a number of different ligands such as the complement component C1q, the growth factor FGF2, the extracellular matrix component ...

Gene and Protein Organization

The human ptx3 gene is located on chromosome 3, band q25 and is organized in three exons coding respectively for the leader peptide, the N-terminal domain and the C-terminal pentraxin like-domain of the protein. PTX3 protein is 381 amino acids long, including a signal peptide of 17 amino acids, and it has a predicted molecular weight of 40,165 Da. The C-terminal domain contains the pentraxin signature, two conserved cysteines (Cys210 and Cys271) and a N-linked glycosylation site at Asn220. PTX3 protomers are assembled to form multimers predominantly of 440 kDa apparent molecular mass, corresponding to decamers. In contrast to what was observed for CRP and SAP pentamers, the decameric form of PTX3 is dependent upon interchain disulfide bonds, as demonstrated by nonreducing SDS-PAGE.164

A murine ptx3 has been also described: the murine gene is located on chromosome 3, in a region (q24-28) homologous to human chromosome 3q, and has the same genomic organization in three exons and two introns as the human counterpart.174 Human and murine PTX3 are highly conserved: both proteins are 381 amino acids long and share 82% of identical amino acids and 92% of conserved amino acids.

A model for PTX3 tertiary folding has been proposed based in part on the sequence homology with CRP and SAP. According to this model, PTX3 pentraxin domain well accommodates on the tertiary fold of SAP, with almost all of the β-strands and the α-helical segments conserved.174

PTX3 is produced by a variety of cell types, including mononuclear phagocytes, dendritic cells (DC), fibroblasts, endothelial cells, smooth muscle cells, adipocytes, synovial cells, chondrocytes and cells of epithelial origin, such as renal and alveolar cells.161,162,175182 Resting cells generally do not release appreciable levels of the protein but they can be triggered to produce PTX3 by primary inflammatory signals, such as TNFα and IL-1β, toll-like receptor (TLR) ligands and microbial moieties, such as LPS, lipoarabinomannans and outer membrane proteins.1,169

Myelomonocytic DCs are major producer of PTX3 in vitro in response to TLR engagement while plasmacytoid DCs do not produce PTX3.183 On the other side, PTX3 can regulate the maturation program of DCs as well as the secretion of soluble factors such as IL-10 and TNF-α, behaving as a flexible regulator of the function of this cell population.184 IFNγ and IL-10 play divergent effects on regulation of PTX3 production by DCs: IFN-γ, which has generally a synergistic effect with LPS, inhibits LPS induction of PTX3 while IL-10 amplifies the response to LPS, TLR ligands and IL-1β.185,186 Production of PTX3 by IL-10-treated DCs is likely to be associated with matrix deposition, considering the role of IL-10 in the induction of a genetic program related to tissue remodeling.

Role in Female Fertility

Ptx3-deficiency in mice is associated with a severe defect in female fertility.168,173 Infertility is due to fertilization failure in vivo and is associated with an abnormal cumulus oophorus expansion. The oocyte develops normally in the absence of PTX3 and can be fertilized in vitro, but the unstable cumulus ECM, in which cumulus cells are uniformly dispersed instead of radiating out from a central oocyte, accounts for fertilization defect in vivo. Cumulus granulosa cells express PTX3 mRNA during the preovulatory period, upon the induction by hormonal ovulatory stimuli as follicle stimulating hormone or human chorionic gonadotropin, and by oocyte derived soluble factors, in particular a member of the TGFβ family, growth differentiation factor-9.167,173 The protein localizes in the ECM, where it plays a crucial role in the assembly of the hyaluronic acid (HA)-rich matrix of the cumulus oophorus.167,187 PTX3 does not interact directly with HA, but it binds TSG-6, which participates in the assembly of the HA-rich matrix. PTX3/TSG-6 complexes might thus serve as an anchoring site for multiple HA molecules, thereby substantially forming a multi-molecular complex that acts as a ‘node’ for cross-linking HA chains. Therefore, PTX3 plays a nonredundant role as structural constituent of the cumulus oophorus ECM essential for in vivo fertilization.

Human cumulus cells express PTX3 as well, and PTX3 protein is present in human cumulus matrix, suggesting that this molecule might have the same role in human female fertility.167,187 Studies have been conducted to assess the potential role of PTX3 as diagnostic marker for oocyte quality: real-time PCR data showed a relatively higher abundance of PTX3 mRNA in cumulus cells from fertilized oocytes compared with cumulus cells from unfertilized oocytes;187 by contrast, PTX3 levels in follicular fluids did not correlate with oocyte quality.188

Results collected over the years on PTX3 levels in patients with a series of inflammatory and infectious disorders (see below) outlined a role of this protein as marker of pathology and prognostic factor, in particular, for conditions reflecting the involvement of the vascular bed. Endothelial dysfunction is a prominent feature of preeclampsia, an important cause of maternal as well as perinatal morbidity and mortality, which may arise in the third trimester of gestation. The pathogenesis of this disease, still not completely defined, is characterized by an excessive maternal inflammatory response; accordingly, significantly higher levels of PTX3 have been found in preeclampsia compared to normal pregnancies.189

Role in Innate Immunity, Inflammation and Apoptotic Cell Clearence

Pathogen recognition is a common feature among the members of the pentraxin family including PTX3 and efforts have been made in order to identify the molecular moieties recognized on bacterial surface. PTX3 does not bind LPS as well as lipoteichoic acid, N-acetylmuramyl-L-alanyl-D-isoglutamine, exotoxin A and enterotoxins A and B. However, it binds with high affinity to recombinant outer membrane protein A from Klebsiella pneumoniae (KpOmpA). KpOmpA binds and activates macrophages and DCs in a TLR2-dependent way, activating a genetic program that includes induction of PTX3. PTX3 in turn binds KpOmpA, and plays a crucial role in the amplification of the inflammatory response to this microbial protein, as demonstrated by the impairment of the inflammatory response induced by KpOmpA in ptx3-deficient mice.169

PTX3 plays an important role in defence against selected pathogens such as Aspergillus fumigatus. This can be explained, at least in part, by an opsonic effect of PTX3, facilitating ingestion of conidia by macrophages.168 Macrophages from PTX3-overexpressing mice have an improved phagocytic activity towards zymosan and Paracoccidioides brasiliensis.170 Moreover, recombinant PTX3 binds to zymosan and P. brasiliensis, and functions as an opsonin, thereby increasing the phagocytic activity of peritoneal macrophages from wild-type animals. These findings provide evidence for a role of PTX3 as a functional ancestor of antibodies and imply the existence of a receptor for this molecule. Accordingly, a binding site has been observed on murine macrophages as well as human mononuclear phagocytes and DCs (Bottazzi, unpublished observations).

Studies in ptx3-deficient mice suggest that the role played by PTX3 in innate resistance is nonredundant and relevant in selected fungal and bacterial infections (A. fumigatus, P. aeruginosa, S. typhimurium) and irrelevant in others (L. monocytogenes, S. aureus, polymicrobic intra-abdominal sepsis) (Garlanda, unpublished observations).168 In particular, extreme susceptibility was observed to invasive pulmonary aspergillosis which was associated with the lack of development of appropriate and protective Th1 anti-fungal responses and to an unbalanced cytokine profile skewed towards a Th2 response.168 The specificity of the defect and the therapeutic potential of PTX3 could be demonstrated by the complete protective effect following treatment with recombinant PTX3.168,190 Variable susceptibility to different pathogens suggests that PTX3 deficiency does not cause a generalized immunodeficiency, and that PTX3 is involved in recognition and resistance against specific microorganisms.

Ptx3 overexpressing and deficient mice were used to evaluate the role of PTX3 in inflammatory conditions. Ptx3 overexpression increases resistance to LPS toxicity and cecal ligation and puncture,171 but induces an exacerbated inflammatory response and reduces survival rate following intestinal ischemia reperfusion injury.172 In a model of kainate-induced seizures, ptx3-deficient mice had more widespread and severe IL-1-induced neuronal damage. In this model PTX3 confers resistance to neurodegeneration, possibly by binding to dying neurons and rescuing them from otherwise irreversible damage.191

Like other members of the pentraxin family,132,192 PTX3 binds apoptotic cells inhibiting their recognition by DCs.184,193 Binding occurs late in the apoptotic process and modulates cytokine production by DC. In addition, preincubation of apoptotic cells with PTX3 enhances C1q binding and C3 deposition on the cell surface, suggesting a role for PTX3 in the complement-mediated clearance of apoptotic cells.165 Moreover, in the presence of dying cells, PTX3 may contribute to editing recognition of apoptotic self versus infectious non self and restricts the cross presentation of antigens derived from dying cells.184 These results suggest that PTX3 has a dual role in the protection against pathogens and in the control of autoimmunity.

Role in Human Pathology

The results obtained in gene-modified mice together with the similarities to a widely used marker of inflammation such as CRP, have given impetus to efforts aimed to investigate the role of PTX3 in diverse human pathologies. PTX3 is expressed at very high levels in the heart of rodents, after systemic administration of microbial products and inflammatory cytokines or ligation of the left coronary artery to model acute myocardial infarction (AMI) (Latini, unpublished observations).174 PTX3 is present in atherosclerotic lesions and is induced by oxidized LDL in smooth muscle cells, moreover PTX3 increases tissue factor expression by mononuclear cells, potentially playing a role in thrombogenesis and wound healing.178,194196 In this context a pilot study was conducted in a small group of patients with AMI, showing that PTX3 plasma levels increase rapidly reaching a peak 6–8 hours after the onset of symptoms.196 In the same context, plasma CRP increased, but it peaked much later, between 24 and 48 hours after symptom onset. Because CRP is produced mainly by the liver in response to IL-6 and PTX3 by the heart and vasculature in response to primary inflammatory stimuli, it was hypothesized that PTX3, rather than CRP, could be an acute-phase reactant more closely related to cardiac injuries such as AMI and therefore could be a sensitive and specific prognostic indicator in this context.197 This hypothesis was confirmed in a recent prospective study on a large group of patients with AMI where it has been shown that PTX3 is an earlier and stronger prognostic marker of death compared to other accepted markers of myocardial necrosis such as creatine kinase and troponin T.198

PTX3 blood levels, barely detectable in normal conditions (1–2 ng/ml), increase rapidly and dramatically (200–800 ng/ml) during a range of pathological conditions others than AMI. Plasma levels of PTX3 are increased in diverse infectious disorders, including sepsis, A. fumigatus infections, active pulmonary tuberculosis and dengue virus infection.168,199201 The higher levels of PTX3 observed in patients with pulmonary tuberculosis or dengue are associated with disease severity and possibly with clinical outcome. Patients with active vasculitis have significantly higher plasma levels of PTX3 than patients with quiescent disease.202 PTX3 inhibition of macrophage phagocytosis of late apoptotic cells could in part explain the phenomenon of leukocytoclasia observed in small vessel vasculitis. PTX3 is also expressed at high levels in patients with systemic juvenile idiopathic arthritis.203

A general feature common to all these pathologies is the rapidity of PTX3 increase compared to CRP: CRP is made in the liver in response primarily to IL-6 while PTX3 is produced locally by a number of different cells in response to proinflammatory signals and thus representing a rapid marker for local activation of inflammation and innate immunity.

Data collected so far in a number of different pathologies indicate a correlation between PTX3 plasma levels and severity of disease, suggesting a possible role of PTX3 as marker of pathology. It remains to be elucidated whether the impressive correlation with outcome and severity actually reflects a role in the pathogenesis of damage, for instance by amplifying the complement and coagulation cascades.

Conclusion

Most suggested functions of short pentraxins CRP and SAP are based on their pattern-recognition characteristics seen in vitro (Table 1). The data on the exact physiological situations in vivo where the short pentraxins would interact with their ligands are beginning to emerge. Likewise, the functional consequences of the recognition properties of CRP and SAP are subjects of current research interests (Fig. 2). Of most importance are the values of CRP in bacterial infections, atherosclerosis and autoimmunity and the value of SAP in amyloidosis. The contribution of the two known effector functions of short pentraxins, that is complement activation and phagocytosis, is under intensive investigation in mouse models of human diseases where these pentraxins have been implicated.

Figure 2
Pentraxins in innate immunity. Inflammation and microbial sensing induce both local and systemic responses characterized by the production of different members of the pentraxin family. Systemic response involves production by the liver of the prototypic ...

Gene targeting of the prototypic, evolutionarily conserved, long pentraxin PTX3 has unequivocally defined the role of this molecule at the crossroad of innate immunity, inflammation, matrix deposition and female fertility (Fig. 1).1 Moreover, recent progress has further defined the structure, regulation, microbial recognition and in vivo function of PTX3.

PTX3 is a component of the complex and complementary network of cellular and humoral pattern recognition receptors involved in the recognition and response to microbial elements and damaged tissues, in tuning inflammatory reactions, in discriminating between infectious nonself and apoptotic self. Translational efforts suggest that PTX3 may represent a new marker of innate immunity and inflammation, rapidly reflecting tissue and vascular bed involvement.

Acknowledgments

This work was supported by National Institutes of Health, USA, and Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero Istruzione Università e Ricerca (MIUR), European Commission.

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