Academic literature on the topic 'Long pentraxin PTX3'

Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and belongs, together with the C-reactive protein (CRP) and other acute phase proteins, to the pentraxins' superfamily: soluble, multifunctional, pattern recognition proteins. Pentraxins share a common C-terminal pentraxin domain, which in the case of PTX3 is coupled to an unrelated long N-terminal domain. PTX3 in humans, like CRP, correlates with surrogate markers of atherosclerosis and is independently associated with the risk of developing vascular events. Studies addressing the potential physiopathological role of CRP in the cardiovascular system were so far inconclusive and have been limited by the fact that the sequence and regulation have not been conserved during evolution between mouse and man. On the contrary, the conservation of sequence, gene organization, and regulation of PTX3 supports the translation of animal model findings in humans. While PTX3 deficiency is associated with increased inflammation, cardiac damage, and atherosclerosis, the overexpression limits carotid restenosis after angioplasty. These observations point to a cardiovascular protective effect of PTX3 potentially associated with the ability of tuning inflammation and favor the hypothesis that the increased levels of PTX3 in subjects with cardiovascular diseases may reflect a protective physiological mechanism, which correlates with the immunoinflammatory response observed in several cardiovascular disorders.

Inflammatory or anti-inflammatory? That is the question as far as the acute-phase response and its mediators, the pentraxins, are concerned. Only some ten years ago, the classical or short pentraxin C-reactive protein and the newly discovered long pentraxin PTX3 were considered to exert most of the detrimental effects of acute inflammation, whether microbial or sterile in origin. However, accumulating evidence suggests an at least dichotomous, context-dependent outcome attributable to the pentraxins, if not a straightforward anti-inflammatory nature of the acute-phase response. This paper is focused on the inherent effects of pentraxin 3 in inflammatory responses, mainly in coronary artery disease and inAspergillus fumigatusinfection. Both are examples of inflammatory reactions in which PTX3 is substantially involved; the former sterile, the latter infectious in origin. Apart from different inducing noxae, similarities in the pathogenesis of the two are striking. All the same, the introductory question still persists: is the ultimate impact of PTX3 in these conditions inflammatory or anti-inflammatory, paradoxical as the latter might appear? We try to provide an answer such as it emerges in the light of recent findings.

Abstract Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.

Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.

Abstract The long pentraxin PTX3 is a soluble pattern recognition receptor produced by monocytes and endothelial cells that plays a nonredundant role in inflammation. Several pathologic conditions are characterized by local production of both PTX3 and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly, PTX3 prevented 125I-FGF2 binding to endothelial cell receptors, leading to specific inhibition of FGF2-induced proliferation. PTX3 hampered also the motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro and their capacity to generate vascular lesions when injected in nude mice. Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast, the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These results establish the selective binding of a member of the pentraxin superfamily to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various physiopathologic conditions driven by inflammation, innate immunity, and/or neoplastic transformation.

Long pentraxin 3 (PTX3) is a newly discovered acute phase protein produced at the sites of infection and inflammation by tissue cells, macrophages, monocytes, and dendritic cells. PTX3 plays an important role in preventing infection of certain fungi, bacteria, and viruses in the lung. Recombinant PTX3 has been proposed as a potential antifungal molecule for therapy. However, under certain experimental conditions, such as intestinal ischemia-reperfusion, high volume mechanical ventilation, or severe bacterial infection, increased expression of PTX3 is associated with more severe lung injury. Therefore, it is necessary to further explore the sources of PTX3 in the lung and the regulatory mechanisms of its expression. It is also essential to further determine how PTX3 binds to pathogens, complement, and apoptotic cells, and to determine whether PTX3 has a specific receptor in targeted cells. These studies will provide insight into the pathological processes of pulmonary infection and acute lung injury and provide potential novel therapeutic strategies to control pulmonary infections without severe lung injury.

Pentraxin 3 (PTX3) is a multifunctional acute phase protein belonging to the family of long pentraxins, which is synthesised in numerous cells of the body under the influence of proinflammatory factors and locally at the site of inflammation. Under physiological conditions, PTX3 is stored in neutrophil granules, where there is a constant pool of glycoproteins. Increased pentraxin 3 levels in blood serum are observed as early as 1 hour after a damaging stimulus. Elevation of PTX3 serum levels can be used to diagnose fertility disorders in women as well as in pregnancy pathology, women at risk of pre-eclampsia, gestational diabetes, premature rupture of membrane and preterm delivery. The biological function of PTX3 is not fully understood, especially in the population of newborns and children. So far, no reference values for PTX3 levels in newborns and children have been developed. This protein can be used as a marker of pulmonary hypertension in newborns as well as to assess the degree of respiratory failure in premature infants. In older children, it is useful in the assessment of the severity of meningococcal disease and sepsis as well as in the treatment of childhood asthma. There are studies available in which blood levels of PTX3 significantly correlate with the severity of kidney damage in Henoch–Schönlein macular degeneration in children, and the evaluation of this protein in urine is used to detect renal parenchymal destruction after pyelonephritis.

Innate immunity represents the first line of defence against pathogens and plays key roles in activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules (PRMs) that recognise pathogen-associated molecular patterns (PAMPs) and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. The long pentraxin PTX3 is a prototypic soluble PRM that is produced at sites of infection and inflammation by both somatic and immune cells. Gene targeting of this evolutionarily conserved protein has revealed a nonredundant role in resistance to selected pathogens. Moreover, PTX3 exerts important functions at the cross-road between innate immunity, inflammation, and female fertility. Here, we review the studies on PTX3, with emphasis on pathogen recognition and cross-talk with other components of the innate immune system.

Bladder tumors are a diffuse type of cancer. Long pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling, and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system, rewiring the immune microenvironment, or acting through mechanisms not yet fully clarified. In this study we used biopsies and data mining to assess that PTX3 is differentially expressed during the different stages of bladder cancer (BC) progression. BC cell lines, representative of different tumor grades, and transgenic/carcinogen-induced models were used to demonstrate in vitro and in vivo that PTX3 production by tumor cells decreases along the progression from low-grade to high-grade advanced muscle invasive forms (MIBC). In vitro and in vivo data revealed for the first time that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness, and drug resistance. PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution. Moreover, FGF/FGFR blockade has an impact on drug resistance and stemness features in BC.

PTX3 is a biomarker of cardiovascular diseases and exerts protective functions in acute myocardial infarction and atherosclerosis. Here we aimed at investigating the role of PTX3 in cardiovascular diseases. First we studied the role of PTX3 in arterial thrombosis induced by FeCl3 injury: PTX3 KO mice showed a 60% reduction in carotid artery blood flow with a greater thrombus formation compared to 20% of WT mice (p<0.01) following arterial thrombosis, an effect mediated by PTX3 derived from non-hematopoietic cells: indeed, PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant increased carotid occlusion compared to WT mice transplanted with bone marrow from WT or PTX3 KO mice (p<0.01). This effect was independent of altered hemostatic properties, impaired platelet activation, modulation of P-selectin activity as P-selectin KO/PTX3 KO mice showed a significant reduction in carotid artery blood flow and increased arterial thrombus formation compared to P-selectin KO (p<0.01). PTX3 was shown to localize between the damaged artery and thrombus and to reduced platelet aggregation induced by collagen and fibrinogen (p>0,01), an effect related mainly to the C-terminal and N-terminal domain respectively. Finally, exogenous administration of hrPTX3 reverted the pro-thrombotic phenotype in PTX3 KO mice and improves the outcomes in WT (p<0.01). In conclusion, PTX3 deficiency is associated with increased arterial thrombosis via modulation of collagen and fibrinogen thrombogenicity. In parallel, we investigated the role of PTX3 in the immune-inflammatory response associated to obesity and metabolic disorders, a condition deeply associated with the incidence of cardiovascular events. After 20 weeks of high fat diet (HFD,45% of calories from fat), PTX3 KO mice compared to WT, showed a decreased weight gain (p<0.05), coupled to a decreased accumulation of fat at both 10 and 20 weeks in the visceral (VAT,p<0.05) and subcutaneous adipose depots (SCAT,p<0.05) measured by magnetic resonance for imaging. Basal glycaemia at both 10 and 20 weeks was similar between groups as well as glucose and insulin tolerance measured by glucose (GTT) and insulin tolerance test (ITT), excluding a direct role of PTX3 on glucose homeostasis. As PTX3 is a key component of innate immunity, we focused our attention on the inflammatory response in VAT of PTX3 KO: adipocyte size was significantly smaller (p<0.01) and associated with a decreased infiltration of leukocytes and expression of pro-inflammatory cytokines (MCP-1, IL-6, p<0.05) compared to WT. These data show that deficiency of PTX3 results in reduced HDF-induced obesity as a consequence of a decreased inflammatory state of PTX3 KO VAT. Concluding, we have shown the dual role of PTX3 which plays a protective role in arterial thrombosis, while in a model of diet-induced obesity is associated with the promotion of inflammation and fat deposition in adipose tissue. This dual role suggests that PTX3 may play different functions depending on the origin and the site of action.

PTX3 is a fluid-phase pattern recognition receptor that participates in innate immunity and inflammation by modulating complement activation, leukocyte recruitment, extracellular matrix deposition and angiogenesis. PTX3 is a biomarker of inflammatory conditions in different pathologies in humans, including acute myocardial infarction to autoimmune diseases, infections and cancer associated inflammation. Moreover, in vivo studies indicate that PTX3 is involved in cancer development, possibly by regulating inflammation. Several tumors lack PTX3 expression, such as human esophageal squamous cell carcinoma, where PTX3 is silenced through pro¬moter hypermethylation. Taken together, these data suggest that PTX3 is potentially involved in cancer development. The aim of this study was to identify the regulatory elements involved in the modulation of PTX3 expression and gain insight into their mechanisms of action in basal condition, inflammatory responses and cancer. Using in silico analysis of PTX3 gene we identified two putative PTX3 enhancers located 230 kbp upstream of the promoter and in the second exon of the gene, overlapping a CpG island, respectively. We performed ChIP assay for histone modifications and epigenetic complexes for the analysis of these genetic elements in human cell lines, before and after treatment with TNFα, that induces PTX3 expression. The results show that these regions are enhancers, but in basal condition are enriched with repressive markers H3K27me3 and polycomb group subunities (SUZ12 and EZH2). After TNFα treatment, the two enhancers became active gaining H3K27ac and the RNA Polymerase II and the first enhancer also acquired the binding for NF-kB. We also analysed the effect of the microRNAs, which were predicted to directly target PTX3, using bioinformatics analysis. miR-9, miR-29 family and miR-181 family were shown to directly target the PTX3 3’-UTR and to significantly reduce both PTX3 mRNA expression and protein production. Luciferase assay with PTX3 promoter and with a reporter vector for NF-kb showed that these miRNAs are also involved in signalling pathways controlling PTX3 transcription. Moreover, RNA Immuno Precipitation assay demonstrated that miR-9, miR-29 family and miR-181 family members and PTX3 mRNA were enriched in the RISC complex of macrophages after 6h of stimulation with lipopolysaccharide. Moreover, inflammatory miRNAs, such as miR-146a, miR-155 and miR-132 regulate PTX3 messenger and protein expression, as well, targeting the network upstream of PTX3 expression. This suggests that PTX3 gene is strictly regulated by several miRNAs acting at different points during inflammatory response. Bioinformatics analysis showed that PTX3 is not express in several cancer, including colorectal cancer (CRC). ELISA and gene expression analysis in CRC cells confirmed bioinformatics data and the treatment with the demethylating agent 5'aza-dC restored PTX3 expression and production. ChIP assay for histone modifications and transcription factors in CRC cells showed that PTX3 enhancers were inactive and they became active after treatment with 5’aza-dC and in response to inflammatory stimuli, thus acquiring the RNA polymerase II and NF-kB. Finally, by Methylated-CpG Island Recovery Assay we analysed the methylation of both promoter and enhancers of PTX3 in different CRC cells and in 40 CRC patients of different tumor stages. Data demonstrated that PTX3 regulatory regions were significantly methylated in all the cell lines and in all tumour stages, compared to their healthy counterparts. Moreover, the methylation started from the adenoma. Taken together, these data show that PTX3 methylation is involved in the inhibition of the PTX3 expression in CRC and suggest that PTX3 may have a protective role in the pathogenesis of this tumour.

The long pentraxin 3 plays a key role in the immunomodulation of diet-induced obesity AIM: Obesity is characterized by a state of chronic low-grade inflammation. PTX3 is the prototype of long pentraxins, it is an essential component of the humoral arm of innate immunity and is involved in many inflammatory processes. There are several conflicting data about the role of PTX3 in obesity. Aim of this project was to clarify whether PTX3 behaves as a bystander or actively participates to obesity-related inflammation. METHODS: PTX3 KO and WT littermates were fed a high fat diet (HFD; 45% Kcal from fat) or a standard fata diet (SFD;10% Kcal from fat) for 20 weeks. Body weight was measured weekly; fat distribution (magnetic resonance for imaging, MRI) and glycemia (glucose-GTT and insulin-ITT tolerance tests) was checked at 10 and 20 weeks. Immunophenotyping and gene expression, in particular of the adipose tissue, was performed at 20 weeks. Ectopic fat deposition in h1/h1 and h2/h2 individuals was determined by DEXA. RESULTS: PTX3 KO mice on HFD exhibit a decreased weight gain compared to WT (AUC weight gain WT=190.8±17.45, KO=134.8±10.09), coupled to a decreased accumulation of visceral (VAT) and subcutaneous (SCAT) fat both at 10 (p<0.05) and 20 weeks (p<0.01) of diet measured by MRI and confirmed weighing the tissues after the sacrifice (VAT% WT=7.609±0.6776, KO=4.390±0.8235; SCAT% WT=5.953±0.9682, KO=3.144±0.6129, p<0.05). Basal glycemia and the results of the glucose and insulin tolerance test were superimposable. PTX3 deficiency results in the reduction of monocytes markers and pro-inflammatory cytokines gene expression in VAT (MCP-1, IL-6, p<0.05) which is associated to a reduced infiltration of monocytes and macrophages in the tissue as assessed by cell sorting. Of note vascularization was enhanced (increased gene expression of Cd31 and Vegfa in VAT, p<0.05) in VAT from PTX3 KO mice. Sorted VAT macrophages showed enhanced expression of molecules associated with M2-polarization (Arg1, Ym-1, p<0.01). In humans, carriers of the h2/h2 haplotype for PTX3, characterized by lower PTX3 plasma levels compared to h1/h1 carriers, presented with lower BMI and lower abdominal obesity compare to h1/h1 carriers (android fat% h2/h2=45.34±10.32, h1/h1=47.17±9.23, p<0.05). CONCLUSIONS: Our results demonstrate that PTX3 might contribute to the development of obesity by limiting adipose tissue vascularization and promoting macrophage infiltration.