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Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1β/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice were more susceptible to invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.

Background Pentraxin3 (PTX3) is an emerging player in lupus nephritis (LN). Anti-PTX3 antibodies showed to delay LN occurrence in vivo. Aim To evaluate renal changes following immunization with PTX3 in a murine model of LN. Materials and methods Twenty-two lupus-prone New Zealand Black/White (NZB/W)F1 mice were divided into two groups (n = 11) and subcutaneously injected with human recombinant (hr)PTX3 100 μg or phosphate buffer saline (PBS) 200 μl, three times 3 weeks apart, starting before development of proteinuria. Five mice from each group were scheduled for sacrifice at week 22 and 6 from each group at week 29. Renal lesions included electron-dense deposits (EDD), glomerular deposition of IgG, complement and PTX3 as markers of renal inflammation. They were evaluated by immunofluorescence (IF), confocal and immunoelectron microscopy (IEM). Validated semiquantitative scores were used when available to score renal lesions. Chi-squared test with Fisher exact test was used for comparison. Results Nineteen out of 22 mice were sacrificed as scheduled. Only hrPTX3-immunized mice developed anti-PTX3 antibodies. Compared to PBS-injected mice, they displayed a dramatic decrease in glomerular deposits of IgG, C1q and PTX3, as well as in the amount of EDD (p = 0.006) and podocyte effacement (p = 0.043). Importantly, PTX3 was pinpointed inside the EDD and co-localized with nuclear material. Conclusions Immunization with PTX3 prevented progression from the preclinical to the clinical stage of LN, inciting anti-PTX3 antibodies and preventing renal PTX3 deposition. PTX3 is a novel component of EDD, submitting it as one initiating autoantigen in LN and as potential target for early treatment.

Background Pentraxin3 (PTX3) is overexpressed in kidneys of patients developing lupus nephritis (LN). Active LN is associated with reduced anti-PTX3 antibodies. However, abnormalities of B cell differentiation against PTX3 have not been characterized in systemic lupus erythematosus (SLE). The aim of our study is to characterize PTX3-specific (PTX3+) B cells in peripheral blood of SLE patients with or without LN and healthy donors (HD). Methods SLE patients without LN, biopsy-proven LN and matched HD were analyzed. Active LN was defined as proteinuria >0.5 g/day or CrCl Results Initially, a flow cytometry based assay to identify PTX3 +B cells was developed by demonstrating simultaneous binding of PTX3-Cy5 and PTX3-PE. Specificity of B cells was validated by blocking experiments using unlabeled PTX3 (figure 1). We could identify circulating PTX3 +B cells in HD and patients. Notably, LN patients showed a significantly diminished number of PTX3 +B cells (SLE vs. LN p=0.033; HD vs. LN p=0.008). This decrease was identified in naive and memory B cell compartments (naive: SLE vs. LN p=0.028; HD vs. LN p=0.0001; memory: SLE vs. LN p=0.038, HD vs. LN p=0.011) (figure 2). Conclusions Decreased PTX3 +B cells in LN within the naive and memory compartment suggest their negative selection at early stages of B cell development potentially related to a decreased regulatory function. PTX3 +B cells could candidate for autoantigen-defined regulatory B cells as a striking abnormality of LN patients

Anti-pentraxin 3 (PTX3) antibodies were associated with the absence of lupus glomerulonephritis in humans.To explore the effects of anti-PTX3 antibodies in New Zealand Black/White (NZB/NZW F1) mice and their inherent mechanisms of action.30 NZB/NZW F1 mice were subdivided into 3 groups of 10 mice each and subcutaneously injected with PTX3, alum and PBS (group 1), alum and PBS (group 2) or PBS alone (group 3), 3 times 3 weeks apart, before development of renal disease. Mice were followed until natural death. Histological analysis and immunohistochemistry were performed on harvested kidneys. Effects of anti-PTX3 antibodies on C1q binding to immobilized PTX3-anti-PTX3 immune complexes were evaluated in vitro using human SLE sera. Qualitative characterization of human IgG anti-PTX3 was performed.Only group 1 mice developed anti-PTX3 antibodies. Anti-dsDNA and anti-C1q antibodies appeared significantly later and at lower levels in group 1 mice vs. controls (p 0.0001). Proteinuria-free and overall survival were significantly increased in group 1 mice vs. controls (p 0.05 and p = 0.03, respectively). Histopathological analysis showed that glomerular and tubular PTX3 staining and renal lesions were increased in controls compared with immunized mice. Addition of human SLE sera positive for anti-PTX3 antibodies to C1q and fixed PTX3 interfered with C1q binding to PTX3-anti-PTX3 immune complexes. Qualitative characterization of human IgG anti-PTX3 showed an increased proportion of IgG4.Anti-PTX3 antibodies delay lupus-like nephritis and prolong survival of NZB/NZW F1 mice. In vitro observations suggest anti-PTX3 antibodies may dampen complement activation via their Fc fragment, likely hindering renal inflammation.

Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte‐secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post‐synaptically silent, suggesting that completion of early synaptogenesis may require a two‐step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally‐active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor‐induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1‐integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N‐terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

Pattern recognition molecules (PRMs) are components of the humoral arm of innate immunity; they recognize pathogen-associated molecular patterns (PAMP) and are functional ancestors of antibodies, promoting complement activation, opsonization, and agglutination. In addition, several PRMs have a regulatory function on inflammation. Pentraxins are a family of evolutionarily conserved PRMs characterized by a cyclic multimeric structure. On the basis of structure, pentraxins have been operationally divided into short and long families. C-reactive protein (CRP) and serum amyloid P component are prototypes of the short pentraxin family, while pentraxin 3 (PTX3) is a prototype of the long pentraxins. PTX3 is produced by somatic and immune cells in response to proinflammatory stimuli and Toll-like receptor engagement, and it interacts with several ligands and exerts multifunctional properties. Unlike CRP, PTX3 gene organization and regulation have been conserved in evolution, thus allowing its pathophysiological roles to be evaluated in genetically modified animals. Here we will briefly review the general properties of CRP and PTX3 as prototypes of short and long pentraxins, respectively, emphasizing in particular the functional role of PTX3 as a prototypic PRM with antibody-like properties.

Chronic lung infections by Pseudomonas aeruginosa strains are a major cause of morbidity and mortality in cystic fibrosis (CF) patients. Although there is no clear evidence for a primary defect in the immune system of CF patients, the host is generally unable to clear P. aeruginosa from the airways. PTX3 is a soluble pattern recognition receptor that plays nonredundant roles in the innate immune response to fungi, bacteria, and viruses. In particular, PTX3 deficiency is associated with increased susceptibility to P. aeruginosa lung infection. To address the potential therapeutic effect of PTX3 in P. aeruginosa lung infection, we established persistent and progressive infections in mice with the RP73 clinical strain RP73 isolated from a CF patient and treated them with recombinant human PTX3. The results indicated that PTX3 has a potential therapeutic effect in P. aeruginosa chronic lung infection by reducing lung colonization, proinflammatory cytokine levels (CXCL1, CXCL2, CCL2, and IL-1β), and leukocyte recruitment in the airways. In models of acute infections and in in vitro assays, the prophagocytic effect of PTX3 was maintained in C1q-deficient mice and was lost in C3- and Fc common γ-chain–deficient mice, suggesting that facilitated recognition and phagocytosis of pathogens through the interplay between complement and FcγRs are involved in the therapeutic effect mediated by PTX3. These data suggested that PTX3 is a potential therapeutic tool in chronic P. aeruginosa lung infections, such as those seen in CF patients.

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule and a key component of the humoral arm of innate immunity. In four different models of tissue damage in mice, PTX3 deficiency was associated with increased fibrin deposition and persistence, and thicker clots, followed by increased collagen deposition, when compared with controls. Ptx3-deficient macrophages showed defective pericellular fibrinolysis in vitro. PTX3-bound fibrinogen/fibrin and plasminogen at acidic pH and increased plasmin-mediated fibrinolysis. The second exon-encoded N-terminal domain of PTX3 recapitulated the activity of the intact molecule. Thus, a prototypic component of humoral innate immunity, PTX3, plays a nonredundant role in the orchestration of tissue repair and remodeling. Tissue acidification resulting from metabolic adaptation during tissue repair sets PTX3 in a tissue remodeling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity.

International audience; Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.

Inflammation is a component of glioma microenvironment. PTX3 is a component of the humoral arm of innate immunity and a candidate marker of inflammation. In the present study we assessed the expression of PTX3 in gliomas by immunohistochemistry. PTX3 expression differed across low and high-grade tumors based on histopathological diagnosis and clinical severity, positively correlating with tumor grade and severity. In a multivariate logistic regression model, only the PTX3 score was significantly associated with the presence of a high-grade tumor. Thus, PTX3 may represent a new marker of cancer-related inflammation and glioma malignancy.

Pattern recognition molecules (PRMs) are components of the humoral arm of innate immunity; they recognize pathogen-associated molecular patterns (PAMP) and are functional ancestors of antibodies, promoting complement activation, opsonization, and agglutination. In addition, several PRMs have a regulatory function on inflammation. Pentraxins are a family of evolutionarily conserved PRMs characterized by a cyclic multimeric structure. On the basis of structure, pentraxins have been operationally divided into short and long families. C-reactive protein (CRP) and serum amyloid P component are prototypes of the short pentraxin family, while pentraxin 3 (PTX3) is a prototype of the long pentraxins. PTX3 is produced by somatic and immune cells in response to proinflammatory stimuli and Toll-like receptor engagement, and it interacts with several ligands and exerts multifunctional properties. Unlike CRP, PTX3 gene organization and regulation have been conserved in evolution, thus allowing its pathophysiological roles to be evaluated in genetically modified animals. Here we will briefly review the general properties of CRP and PTX3 as prototypes of short and long pentraxins, respectively, emphasizing in particular the functional role of PTX3 as a prototypic PRM with antibody-like properties.

Pentraxins are a family of evolutionarily conserved multifunctional patternrecognition proteins characterized by a cyclic multimeric structure. 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 in response to IL-6, while PTX3 is produced by a variety of tissues and cells and in particular by innate immunity cells and endothelial cells in response to proinflammatory signals and Toll-like receptor (TLR) engagement. Structural analysis and gene-modified mice have provided a new level of understanding of the role of pentraxins in immunity, inflammation and homeostasis. Unlike the classic short pentraxins CRP and SAP, whose sequence and regulation have diverged between mouse and man, PTX3 is highly conserved in man and mouse. Thus, results obtained using genetic approaches in the mouse are likely to be informative for the function of PTX3 in man, whereas extrapolation from animals to man is more difficult for CRP and SAP.

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 pathogens 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 non-redundant role in resistance to selected pathogens. Moreover, PTX3 exerts important functions at the crossroad between innate immunity, inflammation and female fertility. Here we review the studies on PTX3, with emphasis on pathogen recognition and crosstalk with other components of the innate immune system.

Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation. RI Russo, Remo/F-9048-2010

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are severe forms of bilateral lung inflammation with poor clinical outcomes. However, the pathophysiology of ALI/ARDS remains largely obscure. Soluble receptor for advanced glycation endproducts (sRAGE) plays a key regulatory role during the acute phase of inflammation, and baseline plasma levels of sRAGE were recently found to be associated with severity of ALI/ARDS. We analyzed, in ALI/ARDS patients, plasma and alveolar levels of sRAGE over time and the association with severity of lung injury. We enrolled 21 ALI/ARDS patients admitted to our intensive care unit (ICU) and assayed plasma sRAGE on the first 2 days after diagnosis, every three days for the first month and then once a week, until ICU discharge or death. We also measured sRAGE levels in bronchoalveolar lavage fluids, obtained when clinically indicated. At each sampling time, we recorded physiological and clinical data of the patients. Plasma sRAGE levels peaked at day 1 and decreased over time. When all samples were considered, plasma and alveolar sRAGE levels were significantly higher in patients with worse oxygenation and higher need for ventilatory support (i.e., patients with more severe lung dysfunction). Moreover, the presence of lung infection yielded higher alveolar sRAGE levels. In conclusion, we show that the plasma and alveolar levels of sRAGE in ALI/ARDS patients are correlated to lung injury severity and to lung infection. Our findings may, in time, lead to the development of more effective therapies against ALI/ARDS. © 2010 Tohoku University Medical Press.

The long pentraxin 3 (PTX3) is a multifunctional soluble pattern recognition receptor, involved in several processes ranging from innate resistance and inflammation to clearance of apoptotic cells and organization of hyaluronic acid-rich extracellular matrices. PTX3 is also a novel marker in several pathological conditions of infectious, inflammatory, or autoimmune origin. This study was designed to assess whether PTX3 is expressed in the male reproductive tract and whether PTX3 interacts with human spermatozoa influencing their function. Here we show for the first time by immunohistochemistry that PTX3 is expressed in the male genital tract in perivascular connective tissue, in endothelial cells, in the interstitium, and in the cytoplasm of prostatic epithelial glandular cells; PTX3 was detectable in seminal plasma in variable levels, which correlated with the percentage of normal spermatozoa. Moreover, PTX3 binds to spermatozoa, in particular with immotile cells, localizing in the neck and in the subacrosomial region. Finally, recombinant PTX3 did not interfere with sperm motility.

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.

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) engagment. 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)-1β and was suppressed by dexamethasone, 1α, 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-γ (IFN-γ). 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-1β 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 α 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-γ 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.