Plasma PTX3, MCP1 and Ang2 are early biomarkers to evaluate the severity of sepsis and septic shock

Sepsis is associated with significant mortality. Early diagnosis and prognosis of patients with sepsis is still a difficult clinical challenge. In this study, the ability of plasma PTX3 (pentraxin 3), MCP1 (monocyte chemoattractant protein 1) and Ang (angiopoietin)1/2 was investigated to evaluate the severity of sepsis. Blood samples were obtained from 43 patients with sepsis. A total of 33 post‐surgery patients with infections and 25 healthy individuals served as controls. The results showed that plasma PTX3, MCP1 and Ang2 significantly increased in patients on the first day of septic shock onset, while sepsis patients had significantly higher Ang2 level, compared with controls. Furthermore, PTX3, MCP1 and Ang2 had high AUROC values in patients with septic shock on the first day of sepsis onset. The findings suggest that PTX3, MCP1 and Ang2 maybe early predictors to evaluate the severity of sepsis and septic shock with the latest Sepsis 3.0 definitions.     

The role of long pentraxin 3, a new inflammatory mediator in inflammatory responses]

Pentraxin 3 (PTX3) is suggested to play important roles in the innate resistance against pathogens, regulation of inflammatory reactions, and clearance of apoptotic cells. PTX3 is the first long pentraxin identified. Long pentraxin shares a C-terminal pentraxin domain with the classical short pentraxin (C-reactive protein, serum amyloid P), but holds an unrelated N-terminal domain that is unique to the long pentraxin. While the short pentraxin is produced only in the liver, PTX3 is made by diverse types of cells, prominently endothelial cells and macrophage, in response to inflammatory signals. Unlike the short pentraxin, the expression of PTX3 in multiple types of tissue cells implies a mechanism for local amplification of innate resistance at the site of infection and inflammation. PTX3 plasma levels are very low in normal subjects but are rapidly increased by inflammatory conditions resulting from a wide range of diseased states, from infection to autoimmune and degenerative disorders. Critically ill patients show elevated circulating levels of PTX3 which are determined by the severity of the disease. Clinical evidence has demonstrated that the elevated PTX3 levels might be a useful early and sensitive marker for severely ill patients. Further studies will definitely be needed to deepen our understanding of PTX3.     

PTX3 as a paradigm for the interaction of pentraxins with the Complement system

Pentraxins are highly conserved components of the humoral arm of innate immunity. They include the short pentraxins C reactive protein (CRP) and serum amyloid P component (SAP), and the long pentraxin PTX3. These are soluble pattern-recognition molecules that are present in the blood and body fluids, and share the ability to recognize pathogens and promote their disposal. CRP and SAP are produced systemically in the liver while PTX3 is produced locally in a number of tissues, macrophages and neutrophils being major sources of this long pentraxin. Pentraxins interact with components of the classical and lectin pathways of Complement as well as with Complement regulators. In particular, PTX3 recognizes C1q, factor H, MBL and ficolins, where these interactions amplify the repertoire of microbial recognition and effector functions of the Complement system. The complex interaction of pentraxins with the Complement system at different levels has broad implications for host defence and regulation of inflammation.     

Production of the soluble pattern recognition receptor PTX3 by myeloid, but not plasmacytoid, dendritic cells

PTX3 is a prototypic of long pentraxin consisting of an N-terminal portion coupled to a C-terminal pentraxin domain, the latter related to short pentraxins (C-reactive protein and serum amyloid P component). PTX3 is a soluble pattern recognition receptor, which plays a non-redundant role in resistance against selected pathogens and in female fertility. The present study was designed to analyze the production of PTX3 by human dendritic cells (DC) and to define the role of different innate immunity receptors in its induction. Human monocyte-derived DC produced copious amounts of PTX3in response to microbial ligands engaging different members of the Toll-like receptor (TLR) family (TLR1 through TLR6), whereas engagement of the mannose receptor had no substantial effect. DC werebetter producers of PTX3 than monocytes and macrophages. Freshly isolated peripheral blood myeloid DC produced PTX3 in response to diverse microbial stimuli. In contrast, plasmacytoid DC exposed to influenza virus or to CpG oligodeoxynucleotides engaging TLR9, did not produce PTX3. PTX3-expressing DC were present in inflammatory lymph nodes from HIV-infected patients. These results suggest that DC of myelomonocytic origin are a major source of PTX3, a molecule which facilitates pathogen recognition and subsequent activation of innate and adaptive immunity.     

The yin-yang of long pentraxin PTX3 in inflammation and immunity

Pentraxins are a family of multimeric proteins characterized by the presence of a pentraxin signature in their C-terminus region. Based on the primary structure, pentraxins are divided into short and long pentraxin: C-reactive protein (CRP) is the prototype of the short pentraxin subfamily while pentraxin 3 (PTX3) is the prototypic long pentraxin. Despite these two molecules exert similar fundamental actions in the regulation of innate immune and inflammatory responses, several differences exist between CRP and PTX3, including gene organization, protein oligomerization and expression pattern. The pathophysiological roles of PTX3 have been investigated using genetically modified mice since PTX3 gene organization and regulation are well conserved between mouse and human. Such in vivo studies figured out that PTX3 mainly have host-protective effects, even if it could also exert negative effects under certain pathophysiologic conditions. Here we will review the general properties of CRP and PTX3, emphasizing the differences between the two molecules and the regulatory functions exerted by PTX3 in innate immunity and inflammation.     

Elevation of plasma levels of the long pentraxin 3 precedes preeclampsia in pregnant patients with type 1 diabetes

Pregnancy complications, such as preeclampsia (PEc), have an increased incidence among patients with type 1 diabetes (T1DM), possibly because of maternal vascular involvement. The prototypic long pentraxin, pentraxin 3 (PTX3) is an acute phase reactant critically associated with vascular injury. PTX3 concentrations selectively increase in pregnant women with PEc. Here, we measured PTX3 levels in 37 consecutive pregnant patients with T1DM. Compared with PTX3 levels in healthy pregnant women at identical gestational ages, PTX3 was significantly elevated in pregnant women with diabetes. Patients with pre-existing nephropathy, a well-characterized microvascular complication of diabetes, have even higher PTX3 concentrations and worse maternal and fetal outcomes. Six/thirty-four diabetic non-nephropatic patients developed PEc: PTX3 levels rose abruptly weeks before PEc manifested (p = 0.0375). PTX3 may represent a valuable marker for early detection and prediction of PEc in patients with T1DM.     

The long pentraxin PTX3 as a link among innate immunity, inflammation, and female fertility

The long pentraxin 3 (PTX3) is member of a complex superfamily of multifunctional proteins characterized by a cyclic multimeric structure. PTX3 is highly conserved in evolution and is produced by innate-immunity cells in response to proinflammatory signals and Toll-like receptor engagement. PTX3 plays complex, nonredundant functions in vivo, acting as a predecessor of antibodies, recognizing microbes, activating complement, facilitating pathogen recognition by phagocytes, and hence, playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional, soluble pattern recognition receptor acting as a nonredundant component of the humoral arm of innate immunity and involved in matrix deposition and female fertility.     

Elevated plasma pentraxin 3: a potential cardiovascular risk factor?

Cardiovascular disease (CVD) is still a primary cause of death in most countries. The pathogenesis of CVD can be influenced by multiple risk factors. Recent studies suggested that the innate immune system may be involved in the development of CVD. Pentraxins are critical components of the innate immune system. Recent researches have demonstrated that elevated plasma pentraxin 3 (PTX3) is associated with cardiovascular events and cardiovascular risk factors. Thus, we hypothesized that elevated plasma PTX3 is a potential cardiovascular risk factor evidenced by the following aspects: (1) PTX3 inhibited angiogenesis and promoted restenosis, (2) the expression of PTX3 increased in advanced atherosclerotic lesions and the blood of patients with ischemic heart disorders, (3) elevated plasma PTX3 levels were associated with adverse cardiovascular outcomes. If the hypothesis is confirmed, PTX3 will be an effective target point to the prevention and treatment of CVD.     

Perspectives on long pentraxin 3 and rheumatoid arthritis: several potential breakthrough points relying on study foundation of the past

Rheumatoid arthritis (RA) is a systemic chronic autoimmune inflammatory disease which is mainly characterized by synovitis and results in a severe burden for both the individual and society. To date, the underlying mechanisms of RA are still poorly understood. Pentraxin 3 (PTX3) is a typical long pentraxin protein which has been highly conserved during evolution. Meanwhile, functions as well as properties of PTX3 have been extensively studied. Several studies identified that PTX3 plays a predominate role in infection, inflammation, immunity and tumor. Interestingly, PTX3 has also been verified to be closely associated with development of RA. We therefore accomplished an elaboration of the relationships between PTX3 and RA. Herein, we mainly focus on the associated cell types and cognate cytokines involved in RA, in combination with PTX3. This review infers the insight into the interaction of PTX3 in RA and aims to provide novel clues for potential therapeutic target of RA in clinic.     

Biology of Human Pentraxin 3 (PTX3) in Acute and Chronic Kidney Disease

The pentraxin superfamily consists of highly conserved multimeric pattern recognition proteins, which are components of the humoral arm of innate immunity. Besides the classical pentraxins (C-reactive protein and serum amyloid P component), pentraxin 3 (PTX3) is a prototypic long pentraxin. In response to primary inflammatory signals, this multifunctional acute phase protein is produced by a variety of cell types. Recently, several clinical studies have demonstrated that PTX3 is significantly associated with kidney dysfunction and disease activity or severity in various inflammatory, cardiovascular and autoimmune diseases. In this paper, we will review the general characteristics of PTX3 focusing in particular on its fundamental biological functions in the course of acute and chronic kidney diseases.     

Long pentraxin 3 (PTX3) expression and release by neutrophils in vitro and in ulcerative colitis

Pentraxin 3 (PTX3) is the first identified long pentraxin, and it is rapidly produced and released by several cell types in response to proinflammatory signals. The aim of this study was to investigate the behavior of neutrophils to produce PTX3 protein in response to proinflammatory cytokine IL-8 in vitro, as well as identify the expression pattern of PTX3 in human ulcerative colitis lesions. Pentraxin 3 protein was found to be present following release upon IL-8 stimulation in cultured neutrophils together with lactoferrin(+)-specific granules localized in neutrophil extracellular traps (NETs) formed by extruded DNA. Neutrophils in colonic mucosal tissue of patients with ulcerative colitis were the main cellular source of PTX3 protein, the expression of which is correlated well with the histological grades of inflammation. Immunofluorescence analysis against anti-lactoferrin antibody revealed the formation of NETs released from neutrophils within crypt abscess lesions, which were found to be activated through the expression of IL-8 receptor B (CXCR2). Of interest, neutrophils depleted of PTX3 protein were displayed, supporting the release of PTX3 from neutrophils in crypt abscess. We suspected that PTX3 protein may contribute to cell-mediated immune defense in inflamed colon tissue, and in particular in crypt abscess lesions, of patients with ulcerative colitis.     

Interferon‐α coincides with suppressed levels of pentraxin‐3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro

Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)‐α is typically elevated during SLE flares, and inhibits hepatocyte production of the pentraxin ‘C‐reactive protein’ (CRP), partly explaining the poor correlation between CRP levels and SLE disease activity. The extrahepatically produced ‘pentraxin 3’ (PTX3) shares waste disposal functions with CRP, but has not been studied extensively in SLE. We analysed serum PTX3 in SLE, and assessed its interference with IFN‐α in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN‐α, and genotyped for three PTX3 single nucleotide polymorphisms reported previously to associate with PTX3 levels. Stimulated PTX3 release was assessed in the presence or absence of IFN‐α in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (P < 0·0001) and correlated with leucocyte variables. Patients with undetectable IFN‐α had 29% higher median PTX3 level than patients with detectable IFN‐α (P = 0·01). PTX3 production by PBMC was inhibited by IFN‐α, whereas neutrophil degranulation of PTX3 was increased. No differences in PTX3 levels were observed between the SNPs. In conclusion, median serum PTX3 is lower in SLE (especially when IFN‐α is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN‐α also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.     

Pentraxins as a key component of innate immunity

Pentraxins are a complex superfamily of multifunctional molecules characterized by a multimeric structure. C-reactive protein and pentraxin 3 (PTX3) are prototypic molecules of the short and long pentraxin family, respectively. PTX3 is conserved in evolution and produced by innate immune cells. Evidence suggests that PTX3 acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation.     

Selective induction of pentraxin 3, a soluble innate immune pattern recognition receptor, in infectious episodes in patients with haematological malignancy

Pentraxins are a superfamily of conserved proteins induced in response to microbial and inflammatory stimuli. Members of this family include C-reactive protein (CRP) and serum amyloid P component, collectively known as the classical short pentraxins, and the more recently discovered pentraxin 3 (PTX3), a member of the closely related subfamily of the long pentraxins. PTX3 has been shown to be produced in response to microbial infections, and highly elevated levels were reported in patients with sepsis. In this study, PTX3 levels were evaluated in sera of a group of patients with haematological malignancy. Our findings indicate that serum PTX3 was elevated in only 1/11 afebrile episodes, despite evidence of mucositis (median 1.39), in 10/10 episodes of blood stream or target organ infections (median 7.2) but, surprisingly, was normal in 5/5 episodes of invasive aspergillosis (median 1.39). The data suggest that serum PTX3 levels are elevated selectively in response to infection. These disparate responses require further study.     

正五聚蛋白 3在炎症及自身免疫中的作用

 PTX3(Pentraxin 3)作为一种可溶性模式识别受体,参与了免疫防御、炎症反应、细胞凋亡、血管重塑、女性生殖生育及血管内皮损伤等多种生理及病理效应。并可作为临床检测自身免疫性疾病中组织损伤,炎症状态严重性和活动性的一项敏感的生物学标记。其具体的作用机制仍然不明。PTX3在多数情况下,限制炎症及自身免疫的发生发展,而起到保护性效应。     

Expression of pentraxin 3 (PTX3) in human atherosclerotic lesions

Pentraxin 3 (PTX3) and C-reactive protein (CRP) are members of the pentraxin superfamily. PTX3 expression is induced in response to inflammatory signals, and is produced at sites of inflammation by several types of cell, primarily monocytes/macrophages, dendritic cells (DCs), endothelial cells, smooth muscle cells (SMCs), and fibroblasts, but is not produced by hepatocytes, which are a major source of CRP. The aim of our study was to investigate the expression pattern of PTX3 in human atherosclerotic lesions using a novel monoclonal antibody against PTX3. We examined coronary arterial thrombi containing an atherosclerotic plaque component removed from patients with acute myocardial infarction and human aortic tissues with various degrees of atherosclerosis sampled from autopsy cases. Immunohistochemical study of paraffin and frozen sections indicated that macrophages, mainly foam cells, expressed PTX3 in advanced atherosclerotic lesions. Interestingly, we also clearly observed PTX3-positive neutrophils infiltrating into atherosclerotic plaques, suggesting that PTX3 derived from neutrophils as well as macrophages plays an important role in atherogenesis.     

Biochemical and functional characterization of the interaction between pentraxin 3 and C1q

Pentraxin 3 (PTX3) is a recently characterized member of the pentraxin family of acute-phase proteins produced during inflammation. Classical short pentraxins, C-reactive protein, and serum amyloid P component can bind to C1q and thereby activate the classical complement pathway. Since PTX3 can also bind C1q, the present study was designed to define the interaction between PTX3 and C1q and to examine the functional consequences of this interaction. A dose-dependent binding of both C1q and the C1 complex to PTX3 was observed. Experiments with recombinant globular head domains of human C1q A, B, and C chains indicated that C1q interacts with PTX3 via its globular head region. Binding of C1q to immobilized PTX3 induced activation of the classical complement pathway as assessed by C4 deposition. Furthermore, PTX3 enhanced C1q binding and complement activation on apoptotic cells. However, in the fluid-phase, pre-incubation of PTX3 with C1q resulted in inhibition of complement activation by blocking the interaction of C1q with immunoglobulins. These results indicate that PTX3 can both inhibit and activate the classical complement pathway by binding C1q, depending on the way it is presented. PTX3 may therefore be involved in the regulation of the innate immune response.     

Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-gamma

The protopypic long pentraxin 3 (PTX3) is a unique, humoral pattern-recognition receptor, which plays a nonredundant function in innate resistance to pathogens. Dendritic cells (DC) of myelomonocytic origin, but not plasmacytoid DC, are a major source of PTX3 in response to Toll-like receptor (TLR) engagement. The present study was designed to explore the regulation of PTX3 production in DC. PTX3 production was induced by TLR ligands, CD40 ligand, and interleukin (IL)-1beta and was suppressed by dexamethasone, 1alpha, 25-dihydroxivitamin D3, and prostaglandin E2. It was unexpected that lipopolysaccharide (LPS)-stimulated PTX3 production was enhanced by IL-10 and inhibited by IL-4 and interferon-gamma (IFN-gamma). Enhancement of PTX3 production by IL-10 was also evident when Pam3 Cys-Ser-(Lys)4.3HCl, a TLR2-TLR1 agonist, polyionisicpolycytidylic acid, a TLR3 agonist, and IL-1beta were used as stimuli. The effect of IL-10 was blocked by an anti-IL-10 monoclonal antibody (mAb) or an anti-IL-10 receptor alpha mAb, which also reduced the LPS-induced production. Thus, production of PTX3 in DC is subjected to a distinct regulatory network, with inhibition by IFN-gamma and enhancement by IL-10. The amplification by IL-10 of production of a nonredundant component of fluid-phase innate immunity mirrors the IL-10 stimulatory function on B cells in adaptive immunity. As PTX3 is also an extracellular matrix component, IL-10-enhanced PTX3 production may play a role in orchestration of tissue remodeling in chronic inflammation.     

Current understanding of PTX3 protective activity on Aspergillus fumigatus infection

Infection caused by Aspergillus fumigatus remains a major therapeutic challenge in immunocompromised individuals. Innate immunity represents the first line of defense against pathogens. In the last 20 years, several proteins belonging to this arm of the immune system have been characterized as being endowed with antifungal activity. Among these, the prototype long pentraxin PTX3 has been identified as a non-redundant protective factor against infections caused by A. fumigatus. A number of relevant animal models of invasive aspergillosis have indicated that PTX3 exerts its protective activity in several conditions of immunosuppression. In this article, we review the current understanding of PTX3 mechanisms of action that might be of help in further exploration of the pharmacological activity of this protein against A. fumigatus.     

Pentraxins in the activation and regulation of innate immunity

Humoral fluid phase pattern recognition molecules (PRMs) are a key component of the activation and regulation of innate immunity. Humoral PRMs are diverse. We focused on the long pentraxin PTX3 as a paradigmatic example of fluid phase PRMs. PTX3 acts as a functional ancestor of antibodies and plays a non-redundant role in resistance against selected microbes in mouse and man and in the regulation of inflammation. This molecule interacts with complement components, thus modulating complement activation. In particular, PTX3 regulates complement-driven macrophage-mediated tumor progression, acting as an extrinsic oncosuppressor in preclinical models and selected human tumors. Evidence collected over the years suggests that PTX3 is a biomarker and potential therapeutic agent in humans, and pave the way to translation of this molecule into the clinic.