47 results on '"Bottazzi, Barbara"'
Search Results
2. Structural insights into the biological functions of the long pentraxin PTX3.
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Massimino, Anna Margherita, Colella, Filippo Emanuele, Bottazzi, Barbara, and Inforzato, Antonio
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PENTRAXINS ,CYTOSKELETAL proteins ,COMPLEMENT activation ,PATTERN perception ,TISSUE remodeling - Abstract
Soluble pattern recognition molecules (PRMs) are a heterogenous group of proteins that recognize pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively), and cooperate with cell-borne receptors in the orchestration of innate and adaptive immune responses to pathogenic insults and tissue damage. Amongst soluble PRMs, pentraxins are a family of highly conserved proteins with distinctive structural features. Originally identified in the early 1990s as an early inflammatory gene, PTX3 is the prototype of long pentraxins. Unlike the short pentraxin C reactive protein (CRP), whose expression is mostly confined to the liver, PTX3 is made by several immune and non-immune cells at sites of infection and inflammation, where it intercepts fundamental aspects of infection immunity, inflammation, and tissue remodeling. Of note, PTX3 cross talks to components of the complement system to control cancer-related inflammation and disposal of pathogens. Also, it is an essential component of inflammatory extracellular matrices (ECMs) through crosslinking of hyaluronic acid and turn-over of provisional fibrin networks that assemble at sites of tissue injury. This functional diversity is mediated by unique structural characteristics whose fine details have been unveiled only recently. Here, we revisit the structure/function relationships of this long pentraxin in light of the most recent advances in its structural biology, with a focus on the interplay with complement and the emerging roles as a component of the ECM. Differences to and similarities with the short pentraxins are highlighted and discussed. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Pentraxins in Humoral Innate Immunity
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Inforzato, Antonio, Bottazzi, Barbara, Garlanda, Cecilia, Valentino, Sonia, Mantovani, Alberto, Lambris, John D., editor, and Hajishengallis, George, editor
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- 2012
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4. The natural FGF-trap long pentraxin 3 inhibits lymphangiogenesis and lymphatic dissemination.
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Turati, Marta, Giacomini, Arianna, Rezzola, Sara, Maccarinelli, Federica, Gazzaroli, Giorgia, Valentino, Sonia, Bottazzi, Barbara, Presta, Marco, and Ronca, Roberto
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PENTRAXINS ,FIBROBLAST growth factors ,VASCULAR endothelial growth factors ,PATTERN perception receptors ,CARDIOVASCULAR system ,CANCER invasiveness - Abstract
The lymphatic vascular system represents a major route for dissemination of several solid tumors, including melanoma. Even though the members of the Vascular Endothelial Growth Factor family VEGF-C and VEGF-A have been shown to drive tumor lymphangiogenesis, experimental evidence indicates that also the pro-angiogenic factor Fibroblast Growth Factor-2 (FGF2) may play a role in the lymphangiogenic switch by triggering the activation of lymphatic endothelial cells (LECs) in cooperation with VEGFs. The soluble pattern recognition receptor Long Pentraxin 3 (PTX3) acts as a natural FGF trap, thus exerting an oncosuppressive role in FGF-dependent tumors. Here, the capacity of PTX3 to modulate lymphangiogenesis was assessed in vitro and in vivo. The results demonstrate that recombinant human PTX3 inhibits the lymphangiogenic activity exerted by the VEGF-A/FGF2/sphingosine-1-phosphate (VFS) cocktail on human and murine LECs. In keeping with in vitro data, a reduced lymphangiogenic response was observed in a lymphangiogenic Matrigel plug assay following the subcutaneous injection of the VFS cocktail in PTX3-overexpressing transgenic TgN(Tie2-hPTX3) mice when compared to wild-type or Ptx3 null animals. Accordingly, the capacity of B16F10-VEGFC-luc melanoma cells to colonize the primary tumor-draining lymph node after grafting into the foot pad was dramatically impaired in PTX3-overexpressing mice. Together with the observation that both the VFS cocktail and melanoma cell conditioned media caused a significant downregulation of PTX3 expression in LECs, these data indicate that the FGF trap activity of PTX3 may exert a key effect in the modulation of lymphangiogenesis and tumor metastatic dissemination. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Pentraxins in innate immunity: lessons from PTX3
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Deban, Livija, Jaillon, Sebastien, Garlanda, Cecilia, Bottazzi, Barbara, and Mantovani, Alberto
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- 2011
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6. Complementary Roles of Short and Long Pentraxins in the Complement-Mediated Immune Response to Aspergillus fumigatus Infections.
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Parente, Raffaella, Possetti, Valentina, Erreni, Marco, D'Autilia, Francesca, Bottazzi, Barbara, Garlanda, Cecilia, Mantovani, Alberto, Inforzato, Antonio, and Doni, Andrea
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PENTRAXINS ,PHAGOCYTOSIS ,ASPERGILLUS fumigatus ,ASPERGILLOSIS ,IMMUNE response ,PATTERN perception receptors - Abstract
The ubiquitous mold Aspergillus fumigatus is the major etiologic agent of invasive aspergillosis, a life-threatening infection amongst immune compromised individuals. An increasing body of evidence indicates that effective disposal of A. fumigatus requires the coordinate action of both cellular and humoral components of the innate immune system. Early recognition of the fungal pathogen, in particular, is mediated by a set of diverse soluble pattern recognition molecules (PRMs) that act as "ancestral antibodies" inasmuch as they are endowed with opsonic, pro-phagocytic and killing properties. Pivotal is, in this respect, the contribution of the complement system, which functionally cooperates with cell-borne pattern recognition receptors (PRRs) and other soluble PRMs, including pentraxins. Indeed, complement and pentraxins form an integrated system with crosstalk, synergism, and regulation, which stands as a paradigm of the interplay between PRMs in the mounting and orchestration of antifungal immunity. Following upon our past experience with the long pentraxin PTX3, a well-established immune effector in the host response to A. fumigatus , we recently reported that this fungal pathogen is targeted in vitro and in vivo by the short pentraxin Serum Amyloid P component (SAP) too. Similar to PTX3, SAP promotes phagocytosis and disposal of the fungal pathogen via complement-dependent pathways. However, the two proteins exploit different mechanisms of complement activation and receptor-mediated phagocytosis, which further extends complexity and integration of the complement-pentraxin crosstalk in the immune response to A. fumigatus. Here we revisit this crosstalk in light of the emerging roles of SAP as a novel PRM with antifungal activity. [ABSTRACT FROM AUTHOR]
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- 2021
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7. The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins.
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Parente, Raffaella, Doni, Andrea, Bottazzi, Barbara, Garlanda, Cecilia, and Inforzato, Antonio
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ASPERGILLUS fumigatus ,ASPERGILLOSIS ,PULMONARY aspergillosis ,CROSSTALK ,PENTRAXINS ,PATTERN perception receptors - Abstract
Aspergillosis is a life‐threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host–pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement‐dependent effector with protective functions against A. fumigatus. Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge. [ABSTRACT FROM AUTHOR]
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- 2020
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8. The Long Pentraxin PTX3 in Bone Homeostasis and Pathology.
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Parente, Raffaella, Sobacchi, Cristina, Bottazzi, Barbara, Mantovani, Alberto, Grčevic, Danka, and Inforzato, Antonio
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BONE growth ,FRACTURE healing ,HOMEOSTASIS ,BONE resorption ,PATHOLOGY ,COMPLEMENT receptors ,PERIOSTEUM - Abstract
The innate immune system is equipped with a number of germ-line encoded soluble pattern recognition molecules (PRMs) that collectively mediate the humoral host response to infection and damage in cooperation with cells and tissues of the immune and non-immune compartments. Despite the impressive diversity in structure, source, and regulation across PRMs, these all share remarkably similar functions inasmuch as they recognize microbes and damaged tissues, activate complement, exert opsono-phagocytic activities, and regulate inflammation. The long pentraxin 3 (PTX3) is a prototypic soluble PRM. Long known as a major player in innate immunity, inflammation and matrix remodeling, only recently has PTX3 emerged as a mediator of bone homeostasis in rodents and humans. Ptx3 -targeted mice exhibit reduced trabecular volume during bone development, and impaired callus mineralization following experimental fracture. The murine gene is expressed in vivo by non-hematopoietic periosteal cells in the early phases of fracture healing, and in vitro by maturing osteoblasts. Human osteoblasts do express the PTX3 protein, whose levels positively correlate with bone density in vivo and osteoblast proliferation and maturation in vitro , thus pointing to a role in bone deposition. Contrasting evidence, however, suggest osteoclastogenesis-promoting effects of PTX3, where its expression has been associated with periodontitis, arthritis, and bone metastasis, conditions hallmarked by inflammation and bone resorption. Here, we review past and recent literature on the functions exerted by this long pentraxin in bone biology, with major emphasis on physiological skeletal remodeling, fracture healing, and chronic diseases of the bone. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Pentraxin 3 in Cardiovascular Disease.
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Ristagno, Giuseppe, Fumagalli, Francesca, Bottazzi, Barbara, Mantovani, Alberto, Olivari, Davide, Novelli, Deborah, and Latini, Roberto
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PENTRAXINS ,CARDIOVASCULAR diseases ,MOIETIES (Chemistry) ,BIOLOGICAL tags ,MYOCARDIAL infarction - Abstract
The long pentraxin PTX3 is a member of the pentraxin family produced locally by stromal and myeloid cells in response to proinflammatory signals and microbial moieties. The prototype of the pentraxin family is C reactive protein (CRP), a widely-used biomarker in human pathologies with an inflammatory or infectious origin. Data so far describe PTX3 as a multifunctional protein acting as a functional ancestor of antibodies and playing a regulatory role in inflammation. Cardiovascular disease (CVD) is a leading cause of mortality worldwide, and inflammation is crucial in promoting it. Data from animal models indicate that PTX3 can have cardioprotective and atheroprotective roles regulating inflammation. PTX3 has been investigated in several clinical settings as possible biomarker of CVD. Data collected so far indicate that PTX3 plasma levels rise rapidly in acute myocardial infarction, heart failure and cardiac arrest, reflecting the extent of tissue damage and predicting the risk of mortality. [ABSTRACT FROM AUTHOR]
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- 2019
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10. The Long Pentraxin PTX3 as a Link Between Innate Immunity, Tissue Remodeling, and Cancer.
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Doni, Andrea, Stravalaci, Matteo, Inforzato, Antonio, Magrini, Elena, Mantovani, Alberto, Garlanda, Cecilia, and Bottazzi, Barbara
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PENTRAXINS ,NATURAL immunity ,TISSUE remodeling ,INFLAMMATION ,PHAGOCYTOSIS - Abstract
The innate immune system comprises a cellular and a humoral arm. Humoral pattern recognition molecules include complement components, collectins, ficolins, and pentraxins. These molecules are involved in innate immune responses by recognizing microbial moieties and damaged tissues, activating complement, exerting opsonic activity and facilitating phagocytosis, and regulating inflammation. The long pentraxin PTX3 is a prototypic humoral pattern recognition molecule that, in addition to providing defense against infectious agents, plays several functions in tissue repair and regulation of cancer-related inflammation. Characterization of the PTX3 molecular structure and biochemical properties, and insights into its interactome and multiple roles in tissue damage and remodeling support the view that microbial and matrix recognition are evolutionarily conserved functions of humoral innate immunity molecules. [ABSTRACT FROM AUTHOR]
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- 2019
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11. Interaction of C1q With Pentraxin 3 and IgM Revisited: Mutational Studies With Recombinant C1q Variants.
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Bally, Isabelle, Inforzato, Antonio, Dalonneau, Fabien, Stravalaci, Matteo, Bottazzi, Barbara, Gaboriaud, Christine, and Thielens, Nicole M.
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PENTRAXINS ,IMMUNOGLOBULIN M ,COLLAGEN ,COMPLEMENT activation ,SITE-specific mutagenesis ,SURFACE plasmon resonance - Abstract
Pentraxins and complement defense collagens are soluble recognition proteins that sense pathogens and altered-self elements, and trigger immune responses including complement activation. PTX3 has been shown to interact with the globular recognition domains (gC1q) of the C1q protein of the classical complement pathway, thereby modulating complement activity. The C1q-PTX3 interaction has been characterized previously by site-specific mutagenesis using individual gC1q domains of each of the three C1q chains. The present study is aimed at revisiting this knowledge taking advantage of full-length recombinant C1q. Four mutations targeting exposed amino acid residues in the gC1q domain of each of the C1q chains (Lys
A200 Asp-LysA201 Asp, ArgB108 Asp-ArgB109 Glu, TyrB175 Leu, and LysC170 Glu) were introduced in recombinant C1q and the interaction properties of the mutants were analyzed using surface plasmon resonance. All C1q mutants retained binding to C1r and C1s proteases and mannose-binding lectin-associated serine proteases, indicating that the mutations did not affect the function of the collagen-like regions of C1q. The effect of these mutations on the interaction of C1q with PTX3 and IgM, and both the PTX3- and IgM-mediated activation of the classical complement pathway were investigated. The LysA200 Asp-LysA201 Asp and LysC170 Glu mutants retained partial interaction with PTX3 and IgM, however they triggered efficient complement activation. In contrast, the ArgB108 Asp-ArgB109 Glu mutation abolished C1q binding to PTX3 and IgM, and significantly decreased complement activation. The TyrB175 Leu mutant exhibited decreased PTX3- and IgM-dependent complement activation. Therefore, we provided evidence that, in the context of the full length C1q protein, a key contribution to the interaction with both PTX3 and IgM is given by the B chain Arg residues that line the side of the gC1q heterotrimer, with a minor participation of a Lys residue located at the apex of gC1q. Furthermore, we generated recombinant forms of the human PTX3 protein bearing either D or A at position 48, a polymorphic site of clinical relevance in a number of infections, and observed that both allelic variants equally recognized C1q. [ABSTRACT FROM AUTHOR]- Published
- 2019
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12. Editorial: The Role of Pentraxins: From Inflammation, Tissue Repair and Immunity to Biomarkers.
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Bottazzi, Barbara, Garlanda, Cecilia, and Teixeira, Mauro Martins
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ECULIZUMAB ,ACUTE phase proteins ,PENTRAXINS ,INFLAMMATORY mediators ,IMMUNITY ,INFLAMMATION ,TAKAYASU arteritis ,THROMBOTIC thrombocytopenic purpura ,HUMAN carcinogenesis - Abstract
CRP, SAP and PTX3 are multifunctional molecules mainly produced by inflammatory mediators and tissue injury. They also discuss the complexity of the roles of PTX3 in cancer, suggesting that PTX3 may have different functions on carcinogenesis depending on the tissue and cancer type. It has been shown that SLE patients display high frequencies and titers of anti-PTX3 antibodies, which are inversely correlated with Lupus nephritis (LN) occurrence, suggesting an immunomodulatory capacity of anti-PTX3 antibodies. PTX3 has been proposed as a promising biomarker candidate in sepsis patients since PTX3 plasma concentration increase and persistence has been positively associated with severity and mortality. [Extracted from the article]
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- 2019
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13. The Long Pentraxin 3 Plays a Role in Bone Turnover and Repair.
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Grčević, Danka, Sironi, Marina, Valentino, Sonia, Deban, Livija, Cvija, Hrvoje, Inforzato, Antonio, Kovačić, Nataša, Katavić, Vedran, Kelava, Tomislav, Kalajzić, Ivo, Mantovani, Alberto, and Bottazzi, Barbara
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PENTRAXINS ,BONE injuries ,OSTEOBLASTS - Abstract
Pentraxin 3 (PTX3) is an inflammatory mediator acting as a fluid-phase pattern recognition molecule and playing an essential role in innate immunity and matrix remodeling. Inflammatory mediators also contribute to skeletal homeostasis, operating at multiple levels in physiological and pathological conditions. This study was designed to investigate the role of PTX3 in physiological skeletal remodeling and bone healing. Micro-computed tomography (μCT) and bone histomorphometry of distal femur showed that PTX3 gene-targeted female and male mice (ptx3
-/- ) had lower trabecular bone volume than their wild-type (ptx3+/+ ) littermates (BV/TV by μCT: 3.50 ± 1.31 vs 6.09 ± 1.17 for females, p < 0.0001; BV/TV 9.06 ± 1.89 vs 10.47 ± 1.97 for males, p = 0.0435). In addition, μCT revealed lower trabecular bone volume in second lumbar vertebra of ptx3-/- mice. PTX3 was increasingly expressed during osteoblast maturation in vitro and was able to reverse the negative effect of fibroblast growth factor 2 (FGF2) on osteoblast differentiation. This effect was specific for the N-terminal domain of PTX3 that contains the FGF2-binding site. By using the closed transversal tibial fracture model, we found that ptx3-/- female mice formed significantly less mineralized callus during the anabolic phase following fracture injury compared to ptx3+/+ mice (BV/TV 17.05 ± 4.59 vs 20.47 ± 3.32, p = 0.0195). Nonhematopoietic periosteal cells highly upregulated PTX3 expression during the initial phase of fracture healing, particularly CD51+ and aSma+ osteoprogenitor subsets, and callus tissue exhibited concomitant expression of PTX3 and FGF2 around the fracture site. Thus, PTX3 supports maintenance of the bone mass possibly by inhibiting FGF2 and its negative impact on bone formation. Moreover, PTX3 enables timely occurring sequence of callus mineralization after bone fracture injury. These results indicate that PTX3 plays an important role in bone homeostasis and in proper matrix mineralization during fracture repair, a reflection of the function of this molecule in tissue homeostasis and repair. [ABSTRACT FROM AUTHOR]- Published
- 2018
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14. Inflammatory Long Pentraxin 3 is Associated with Leukocyte Telomere Length in Night-Shift Workers.
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Pavanello, Sofia, Stendardo, Mariarita, Mastrangelo, Giuseppe, Bonci, Melissa, Bottazzi, Barbara, Campisi, Manuela, Nardini, Marco, Leone, Roberto, Mantovani, Alberto, and Boschetto, Piera
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PENTRAXINS ,TELOMERES ,NIGHT work ,PHYSIOLOGY - Abstract
Aging is an emerging worldwide threat to public health, even in the workplace, as it links with risk of illness and death. Bewildered inflammatory responses and stressful conditions associate with age-related disorders. Additionally, circadian rhythm disruption, a critical health issue in night-shift workers, correlates with premature aging. We investigated the hypothesis of a link between altered inflammatory response, detected by plasmatic long pentraxin 3 (PTX3), and biological aging, measured by leukocyte telomere length (LTL), attrition, and possibly induced by night-shift work. Within the framework of a crosssectional study, such possible relationships were appraised by simultaneous equation model (SEM) technique among day and night-shift hospital workers. PTX3 levels, modulated by several aging conditions [i.e., body mass index (BMI) (beta = -0.22; p = 0.022), C-reactive protein (CRP) (beta = -0.07; p = 0.000), and cardiovascular diseases with hypertension included (CVD) (beta = -0.12; p = 0.000)], positively associate with LTL (coefficient = 0.15; p = 0.033). LTL, in turn is reduced by CVD (beta = -0.15; p = 0.000), binge drinking (beta = -0.10; p = 0.004), and CRP (beta = -0.05; p = 0.026). On the other hand, night-shift work, found to be remarkably free from aging risk factors [i.e., age (beta = -0.13; p = 0.017), BMI (beta = -0.17; p = 0.030), CVD (beta = -0.14; p = 0.000), and binge drinking (beta = -0.13; p = 0.000)], does associate almost significantly with reversed PTX3 (coefficient = -0.09; p = 0.089) and even with CRP (beta = 0.17; p = 0.000). In conclusion, the SEM analysis indicates that PTX3 is positively linked to LTL. The finding suggests a possible new role of this long pentraxin that, by orchestrating an efficient governance of inflammatory processes, may protect telomere from attrition, ensuring therefore the genetic stability of cells. The higher CRP levels among night-shift workers suggest that night-shift work is associated with increased systemic inflammation. This would make nocturnal workers more susceptible to premature aging. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
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Deyab, Gia, Hokstad, Ingrid, Whist, Jon Elling, Småstuen, Milada Cvancarova, Agewall, Stefan, Lyberg, Torstein, Bottazzi, Barbara, Meroni, Pier Luigi, Leone, Roberto, Hjeltnes, Gunnbjorg, and Hollan, Ivana
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RHEUMATOID arthritis treatment ,ANTIRHEUMATIC agents ,PENTRAXINS ,PSORIATIC arthritis ,ANKYLOSING spondylitis ,CARDIOVASCULAR diseases risk factors ,BIOMARKERS - Abstract
Background: Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). Methods: We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. Results: s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. Conclusion: IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera.
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Lussana, Federico, Carobbio, Alessandra, Salmoiraghi, Silvia, Guglielmelli, Paola, Vannucchi, Alessandro Maria, Bottazzi, Barbara, Leone, Roberto, Mantovani, Alberto, Barbui, Tiziano, and Rambaldi, Alessandro
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THROMBOCYTOPENIA treatment ,THROMBOCYTOSIS ,PENTRAXINS ,C-reactive protein ,POLYCYTHEMIA treatment ,GENETIC mutation ,GENETICS - Abstract
Background: The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods: We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results: PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions: These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed. [ABSTRACT FROM AUTHOR]
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- 2017
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17. Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial.
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Caironi, Pietro, Masson, Serge, Mauri, Tommaso, Bottazzi, Barbara, Leone, Roberto, Magnoli, Michela, Barlera, Simona, Mamprin, Filippo, Fedele, Andrea, Mantovani, Alberto, Tognoni, Gianni, Pesenti, Antonio, Gattinoni, Luciano, Latini, Roberto, Bruzzone, Paola, Pagan, Francesca, Russo, Riccarda, Confalonieri, Andrea, Abbruzzese, Chiara, and Vergnano, Beatrice
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PENTRAXINS ,SEPSIS ,ALBUMINS ,SEPTIC shock ,PROGNOSIS ,PATIENTS ,DISEASE risk factors - Abstract
Background The long pentraxin PTX3 is a key component of the humoral arm of innate immunity related to sepsis severity and mortality. We evaluated the clinical and prognostic significance of circulating PTX3 in the largest cohort ever reported of patients with severe sepsis or septic shock. Materials and methods Plasma PTX3 was measured on days 1, 2 and 7 after randomization of 958 patients to albumin or crystalloids for fluid resuscitation in the multicentre Albumin Italian Outcome Sepsis (ALBIOS) trial. We tested the association of PTX3 and its changes over time with clinical severity, prevalent and incident organ dysfunctions, 90-day mortality and treatment. Results PTX3 was high at baseline (72 [33-186] ng/mL) and rose with the severity and number of organ dysfunctions ( P < 0·001) and the incidence of subsequent new failures. The PTX3 concentration dropped from day 1 to 7, but this decrease was less pronounced in patients with septic shock ( P = 0·0004). Higher concentrations of PTX3 on day 1 predicted incident organ dysfunctions. Albumin supplementation was associated with lower levels of PTX3 in patients with septic shock ( P = 0·005) but not in those without shock. In a fully adjusted multivariable model, PTX3 on day 7 predicted 90-day mortality. Smaller drops in PTX3 predicted higher 90-day mortality. Conclusions In severe sepsis and septic shock, early high PTX3 predict subsequent new organ failures, while a smaller drop in circulating PTX3 over time predicts an increased risk of death. Patients with septic shock show lower levels of PTX3 when assigned to albumin than to crystalloids. [ABSTRACT FROM AUTHOR]
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- 2017
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18. Endothelial cell-derived pentraxin 3 limits the vasoreparative therapeutic potential of circulating angiogenic cells.
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O'Neill, Christina L., Guduric-Fuchs, Jasenka, Chambers, Sarah E. J., O'Doherty, Michelle, Bottazzi, Barbara, Stitt, Alan W., and Medina, Reinhold J.
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ENDOTHELIAL cells ,PENTRAXINS ,MYOCARDIAL revascularization ,BLOOD-vessel physiology ,VASCULAR endothelial growth factors - Abstract
Aims: Circulating angiogenic cells (CACs) promote revascularization of ischaemic tissues although their underlying mechanism of action and the consequences of delivering varying number of these cells for therapy remain unknown. This study investigates molecular mechanisms underpinning CAC modulation of blood vessel formation. Methods and results: CACs at low (2 x 10
5 cells/mL) and mid (2 x 106 cells/mL) cellular densities significantly enhanced endothelial cell tube formation in vitro, while high density (HD) CACs (2 x 107 cells/mL) significantly inhibited this angiogenic process. In vivo, Matrigel-based angiogenesis assays confirmed mid-density CACs as pro-angiogenic and HD CACs as anti-angiogenic. Secretome characterization of CAC-EC conditioned media identified pentraxin 3 (PTX3) as only present in the HD CAC-EC co-culture. Recombinant PTX3 inhibited endothelial tube formation in vitro and in vivo. Importantly, our data revealed that the anti-angiogenic effect observed in HD CAC-EC co-cultures was significantly abrogated when PTX3 bioactivity was blocked using neutralizing antibodies or PTX3 siRNA in endothelial cells. We show evidence for an endothelial source of PTX3, triggered by exposure to HD CACs. In addition, we confirmed that PTX3 inhibits fibroblast growth factor (FGF) 2-mediated angiogenesis, and that the PTX3 N-terminus, containing the FGF-binding site, is responsible for such anti-angiogenic effects. Conclusion: Endothelium, when exposed to HD CACs, releases PTX3 which markedly impairs the vascular regenerative response in an autocrine manner. Therefore, CAC density and accompanying release of angiocrine PTX3 are critical considerations when using these cells as a cell therapy for ischaemic disease. [ABSTRACT FROM AUTHOR]- Published
- 2016
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19. Pentraxins in the activation and regulation of innate immunity.
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Daigo, Kenji, Inforzato, Antonio, Barajon, Isabella, Garlanda, Cecilia, Bottazzi, Barbara, Meri, Seppo, and Mantovani, Alberto
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PENTRAXINS ,NATURAL immunity ,COMPLEMENT activation ,MACROPHAGES ,TUMOR suppressor proteins ,BIOMARKERS - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2016
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20. The pentraxins PTX3 and SAP in innate immunity, regulation of inflammation and tissue remodelling.
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Bottazzi, Barbara, Inforzato, Antonio, Messa, Massimo, Barbagallo, Marialuisa, Magrini, Elena, Garlanda, Cecilia, and Mantovani, Alberto
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PENTRAXINS , *AMYLOID genetics , *PATIENT management , *LABORATORY mice , *TISSUE analysis - Abstract
Summary Pentraxins are a superfamily of fluid phase pattern recognition molecules conserved in evolution and characterized by a cyclic multimeric structure. C-reactive protein (CRP) and serum amyloid P component (SAP) constitute the short pentraxin arm of the superfamily. CRP and SAP are produced in the liver in response to IL-6 and are acute phase reactants in humans and mice respectively. In addition SAP has been shown to affect tissue remodelling and fibrosis by stabilizing all types of amyloid fibrils and by regulating monocyte to fibrocyte differentiation. Pentraxin 3 (PTX3) is the prototype of the long pentraxin arm. Gene targeted mice and genetic and epigenetic studies in humans suggest that PTX3 plays essential non-redundant roles in innate immunity and inflammation as well as in tissue remodelling. Recent studies have revealed the role of PTX3 as extrinsic oncosuppressor, able to tune cancer-related inflammation. In addition, at acidic pH PTX3 can interact with provisional matrix components promoting inflammatory matrix remodelling. Thus acidification during tissue repair sets PTX3 in a tissue remodelling and repair mode, suggesting that matrix and microbial recognition are common, ancestral features of the humoral arm of innate immunity. [ABSTRACT FROM AUTHOR]
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- 2016
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21. Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis.
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Simon, Amélie, Subra, Jean-François, Guilpain, Philippe, Jeannin, Pascale, Pignon, Pascale, Blanchard, Simon, Garo, Erwan, Jaillon, Sébastien, Chevailler, Alain, Renier, Gilles, Puéchal, Xavier, Bottazzi, Barbara, Mantovani, Alberto, Delneste, Yves, and Augusto, Jean-François
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VASCULITIS ,PENTRAXINS ,AUTOANTIBODIES ,ANTINEUTROPHIL cytoplasmic antibodies ,PROTEIN expression ,ENZYME-linked immunosorbent assay ,PATIENTS - Abstract
Objectives: Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Methods: Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs. Results: Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p<0.001) and, interestingly, in 7 of 14 MPO and PR3 ANCA negative AAV patients. Moreover, by indirect immunofluorescence on fixed neutrophils, anti-PTX3 aAbs gave rise to a specific cytoplasmic fluorescence pattern distinct from the classical cytoplasmic (c-ANCA), perinuclear (p-ANCA), and atypical (a-ANCA) pattern. Anti-PTX3 aAbs levels were higher in patients with active AAV as compared to patients with inactive disease. Conclusion: Our work suggests that PTX3 is as a novel ANCA antigen. Anti-PTX3 aAbs appear thus as a promising novel biomarker in the diagnosis of AAV, including in patients without detectable MPO and PR3 ANCA. [ABSTRACT FROM AUTHOR]
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- 2016
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22. Elevations of inflammatory markers PTX3 and sST2 after resuscitation from cardiac arrest are associated with multiple organ dysfunction syndrome and early death.
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Ristagno, Giuseppe, Varpula, Tero, Masson, Serge, Greco, Marta, Bottazzi, Barbara, Milani, Valentina, Aleksova, Aneta, Sinagra, Gianfranco, Assandri, Roberto, Tiainen, Marjaana, Vaahersalo, Jukka, Kurola, Jouni, Barlera, Simona, Montanelli, Alessandro, Latini, Roberto, Pettilä, Ville, Bendel, Stepani, and Skrifvars, Markus B.
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CARDIAC arrest ,RESUSCITATION ,PENTRAXINS ,C-reactive protein ,INTENSIVE care units ,HOSPITAL admission & discharge - Abstract
Background: A systemic inflammatory response is observed after cardiopulmonary resuscitation. We investigated two novel inflammatory markers, pentraxin 3 (PTX3) and soluble suppression of tumorigenicity 2 (sST2), in comparison with the classic high-sensitivity C-reactive protein (hsCRP), for prediction of early multiple organ dysfunction syndrome (MODS), early death, and long-term outcome after out-of-hospital cardiac arrest. Methods: PTX3, sST2, and hsCRP were assayed at ICU admission and 48 h later in 278 patients. MODS was defined as the 24 h non-neurological Sequential Organ Failure Assessment (SOFA) score ≥ 12. Intensive care unit (ICU) death and 12-month Cerebral Performance Category (CPC) were evaluated. Results: In total, 82% of patients survived to ICU discharge and 48% had favorable neurological outcome at 1 year (CPC 1 or 2). At ICU admission, median plasma levels of hsCRP (2.8 mg/L) were normal, while levels of PTX3 (19.1 ng/mL) and sST2 (117 ng/mL) were markedly elevated. PTX3 and sST2 were higher in patients who developed MODS (p < 0.0001). Admission levels of PTX3 and sST2 were also higher in patients who died in ICU and in those with an unfavorable 12-month neurological outcome (p < 0.01). Admission levels of PTX3 and sST2 were independently associated with subsequent MODS [OR: 1.717 (1.221-2.414) and 1.340, (1.001-1.792), respectively] and with ICU death [OR: 1.536 (1.078-2.187) and 1.452 (1.064-1.981), respectively]. At 48 h, only sST2 and hsCRP were independently associated with ICU death. Conclusions: Higher plasma levels of PTX3 and sST2, but not of hsCRP, at ICU admission were associated with higher risk of MODS and early death. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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23. Recognition of Neisseria meningitidis by the Long Pentraxin PTX3 and Its Role as an Endogenous Adjuvant.
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Bottazzi, Barbara, Santini, Laura, Savino, Silvana, Giuliani, Marzia M., Dueñas Díez, Ana I., Mancuso, Giuseppe, Beninati, Concetta, Sironi, Marina, Valentino, Sonia, Deban, Livija, Garlanda, Cecilia, Teti, Giuseppe, Pizza, Mariagrazia, Rappuoli, Rino, and Mantovani, Alberto
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NEISSERIA meningitidis , *PENTRAXINS , *NATURAL immunity , *CELL membranes , *ANTIGENS , *LABORATORY mice - Abstract
Long pentraxin 3 (PTX3) is a non-redundant component of the humoral arm of innate immunity. The present study was designed to investigate the interaction of PTX3 with Neisseria meningitidis. PTX3 bound acapsular meningococcus, Neisseria-derived outer membrane vesicles (OMV) and 3 selected meningococcal antigens (GNA0667, GNA1030 and GNA2091). PTX3-recognized microbial moieties are conserved structures which fulfil essential microbial functions. Ptx3-deficient mice had a lower antibody response in vaccination protocols with OMV and co-administration of PTX3 increased the antibody response, particularly in Ptx3-deficient mice. Administration of PTX3 reduced the bacterial load in infant rats challenged with Neisseria meningitidis. These results suggest that PTX3 recognizes a set of conserved structures from Neisseria meningitidis and acts as an amplifier/endogenous adjuvant of responses to this bacterium. [ABSTRACT FROM AUTHOR]
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- 2015
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24. A New Surface Plasmon Resonance-Based Immunoassay for Rapid, Reproducible and Sensitive Quantification of Pentraxin-3 in Human Plasma.
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Canovi, Mara, Lucchetti, Jacopo, Stravalaci, Matteo, Valentino, Sonia, Bottazzi, Barbara, Salmona, Mario, Bastone, Antonio, and Gobbi, Marco
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SURFACE plasmon resonance ,PENTRAXINS ,MONOCLONAL antibodies ,SEPSIS ,IMMUNOGLOBULINS - Abstract
A new immunoassay based on surface plasmon resonance (SPR) for the rapid, reproducible and sensitive determination of pentraxin-3 (PTX3) levels in human plasma has been developed and characterized. The method involves a 3-min flow of plasma over a sensor chip pre-coated with a monoclonal anti-PTX3 antibody (MNB4), followed by a 3-min flow of a polyclonal anti-PTX3 antibody (pAb), required for specific recognition of captured PTX3. The SPR signal generated with this secondary antibody linearly correlates with the plasma PTX3 concentration, in the range of 5-1500 ng/mL, with a lowest limit of detection of 5 ng/mL. The PTX3 concentrations determined with the SPR-based immunoassay in the plasma of 21 patients with sepsis, ranging 15-1600 ng/mL, were superimposable to those found in a classic ELISA immunoassay. Since the PTX3 concentration in the plasma of healthy subjects is <2 ng/mL, but markedly rises in certain medical conditions, the method is useful to quantify pathological levels of this important biomarker, with important diagnostic applications. In comparison with the classic ELISA, the SPR-based approach is much faster (30 min versus 4-5 h) and could be exploited for the development of new cost-effective SPR devices for point-of-care diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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25. Multiplexed label-free optical biosensor for medical diagnostics.
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Bottazzi, Barbara, Fornasari, Lucia, Frangolho, Ana, Giudicatti, Silvia, Mantovani, Alberto, Marabelli, Franco, Marchesini, Gerardo, Pellacani, Paola, Therisod, Rita, and Valsesia, Andrea
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BIOSENSOR research , *POLYMERS , *GOLD , *SURFACE plasmon resonance , *POLYELECTROLYTES - Abstract
This paper describes a new multiplexed label-free biosensor. The detection technology is based on nanostructured gold-polymer surfaces. These surfaces support surface plasmon resonance modes that can be probed by a miniaturized optical setup. The optical characterization of the sensing chip shows the sensitivity and the limit-of-detection to refractive index changes. Moreover, by studying the progressive adhesion of molecular monolayers of polyelectrolytes, the decay of the plasmonicmode electric field above the surface has been recon- structed. A multiplexed label-free biosensing device is then described and characterized in terms of sensitivity, lateral resolution, and sensitivity to a model biological assay. The sensitivity in imaging mode of the device is of the order of 10-6 refractive index units, while the measured lateral resolution is 6.25 µm within a field of view of several tenths of mm², making the instrument unique in terms of multiplexing capability. Finally, the proof-of-concept application of the technology as a point-of-care diagnostic tool for an inflammatory marker is demonstrated. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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26. A Single Amino Acid Substitution in the Hemagglutinin of H3N2 Subtype Influenza A Viruses Is Associated with Resistance to the Long Pentraxin PTX3 and Enhanced Virulence in Mice.
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Job, Emma R., Bottazzi, Barbara, Short, Kirsty R., Yi-Mo Deng, Mantovani, Alberto, Brooks, Andrew G., and Reading, Patrick C.
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AMINO acid analysis , *INFLUENZA A virus , *PENTRAXINS , *MICROBIAL virulence -- Immunological aspects , *HEMAGGLUTININ - Abstract
The long pentraxin, pentraxin 3 (PTX3), can play beneficial or detrimental roles during infection and disease by modulating various aspects of the immune system. There is growing evidence to suggest that PTX3 can mediate antiviral activity in vitro and in vivo. Previous studies demonstrated that PTX3 and the short pentraxin serum amyloid P express sialic acids that are recognized by the hemagglutinin (HA) glycoprotein of certain influenza Aviruses (IAV), resulting in virus neutralization and anti-IAVactivity. In this study, we demonstrate that specificity of both HA and the viral neuraminidase for particular sialic acid linkages determines the susceptibility of H1N1, H3N2, and H7N9 strains to the antiviral activities of PTX3 and serum amyloid P. Selection of H3N2 virus mutants resistant to PTX3 allowed for identification of amino acid residues in the vicinity of the receptor-binding pocket of HA that are critical determinants of sensitivity to PTX3; this was supported by sequence analysis of a range of H3N2 strains that were sensitive or resistant to PTX3. In a mouse model of infection, the enhanced virulence of PTX3-resistant mutants was associated with increased virus replication and elevated levels of proinflammatory cytokines in the airways, leading to pulmonary inflammation and lung injury. Together, these studies identify determinants in the viral HA that can be associated with sensitivity to the antiviral activities of PTX3 and highlight its importance in the control of IAV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients.
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Hamon, Yveline, Jaillon, Sébastien, Person, Christine, Giniès, Jean-Louis, Garo, Erwan, Bottazzi, Barbara, Ghamrawi, Sarah, Urban, Thierry, Subra, Jean-François, Bouchara, Jean-Philippe, Mantovani, Alberto, Jeannin, Pascale, and Delneste, Yves
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PROTEOLYTIC enzymes ,PENTRAXINS ,CYSTIC fibrosis ,PATTERN recognition systems ,NATURAL immunity ,PATHOGENIC microorganisms ,LUNG diseases ,ASPERGILLUS fumigatus ,PATIENTS - Abstract
The prototypic long pentraxin PTX3, a soluble pattern recognition receptor, plays an important role in innate defense against selected pathogens by favoring their elimination and the initiation of protective responses. PTX3 has notably beneficial effects in mice infected with Aspergillus fumigatus and Pseudomonas aeruginosa. Cystic fibrosis (CF), a severe inherited autosomal recessive disease, is characterized by recurrent lung infections, especially by these two pathogens. We thus hypothesized that the status of PTX3 may be altered in CF patients. Level and integrity of PTX3 were analyzed in the sputum samples from 51 CF patients and 7 patients with chronic obstructive pulmonary disease (COPD). The levels of PTX3 were increased in serums from CF patients, but low in their respiratory secretions. PTX3 concentrations in sputum samples were dramatically lower in CF patients than in COPD patients. The low concentration of PTX3 resulted from a proteolysis cleavage by elastase and A. fumigatus proteases. Interestingly, the N-ter domain of PTX3, involved in protection against A. fumigatus, is preferentially degraded by these proteases. These results indicate that the selective proteolysis of PTX3 in the CF lung may explain, in part, the recurrent lung infections by PTX3-sensitive pathogens in CF patients. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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28. Increased long-term expression of pentraxin 3 in irradiated human arteries and veins compared to internal controls from free tissue transfers.
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Björklund, Tinna Christersdottir, Reilly, Sarah-Jayne, Gahm, Caroline, Bottazzi, Barbara, Mantovani, Alberto, Tornvall, Per, and Halle, Martin
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CARDIOVASCULAR diseases risk factors ,PENTRAXINS ,BLOOD vessels ,C-reactive protein ,POLYMERASE chain reaction - Abstract
Background: Clinical studies have shown that radiotherapy increases the risk of cardiovascular disease at irradiated sites years after exposure. However, there is a lack of biological explanations in humans. We therefore examined human blood vessels exposed to radiotherapy and studied C-reactive protein (CRP) and pentraxin 3 (PTX3), a new marker for adverse cardiovascular outcome dependent on TNF- alpha (TNFα) or interleukin-1beta (IL-1β) expression. Methods: Pairs of irradiated and non-irradiated human conduit arteries and veins were harvested from the same patient during autologous free tissue transfer for cancer-reconstruction at a median time of 48 weeks after radiotherapy. Differential gene expression was studied using qRT-PCR, confirmed by immunohistochemistry and cellular origins determined by immunofluorescence. Results: Gene expression in irradiated arteries compared to non-irradiated showed a consistent up-regulation of PTX3 in all patients and in a majority of veins (p < 0.001). Both TNFα and IL-1β were increased in irradiated compared to non-irradiated arteries (p < 0.01) and IL-1β correlated to the PTX3 expression (p = 0.017). Immunohistochemical and immunofluorescence staining confirmed an increased expression of PTX3 in endothelial cells, macrophages and smooth muscle cells. Conclusions: The sustained expression of PTX3 in arteries and veins tie biological evidence in humans to clinical studies and encourage further exploration of innate immunity in the pathogenesis of a radiation-induced vasculopathy. Keywords: PTX3, CRP, Radiotherapy, Human, Blood vessels, Gene expression, Cardiovascular disease, Atherosclerosis, [ABSTRACT FROM AUTHOR]
- Published
- 2013
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29. The long pentraxin PTX3: a paradigm for humoral pattern recognition molecules.
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Mantovani, Alberto, Valentino, Sonia, Gentile, Stefania, Inforzato, Antonio, Bottazzi, Barbara, and Garlanda, Cecilia
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PENTRAXINS ,PATTERN recognition systems ,NATURAL immunity ,PATHOGENIC microorganisms ,SERUM ,PATHOLOGICAL physiology - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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30. Serum Amyloid P Is a Sialylated Glycoprotein Inhibitor of Influenza A Viruses.
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Job, Emma R., Bottazzi, Barbara, Gilbertson, Brad, Edenborough, Kathryn M., Brown, Lorena E., Mantovani, Alberto, Brooks, Andrew G., and Reading, Patrick C.
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AMYLOID , *GLYCOPROTEINS , *INFLUENZA A virus , *PENTRAXINS , *NATURAL immunity , *ANTIVIRAL agents , *BLOOD agglutination - Abstract
Members of the pentraxin family, including PTX3 and serum amyloid P component (SAP), have been reported to play a role in innate host defence against a range of microbial pathogens, yet little is known regarding their antiviral activities. In this study, we demonstrate that human SAP binds to human influenza A virus (IAV) strains and mediates a range of antiviral activities, including inhibition of IAV-induced hemagglutination (HA), neutralization of virus infectivity and inhibition of the enzymatic activity of the viral neuraminidase (NA). Characterization of the anti-IAV activity of SAP after periodate or bacterial sialidase treatment demonstrated that α(2,6)-linked sialic acid residues on the glycosidic moiety of SAP are critical for recognition by the HA of susceptible IAV strains. Other proteins of the innate immune system, namely human surfactant protein A and porcine surfactant protein D, have been reported to express sialylated glycans which facilitate inhibition of particular IAV strains, yet the specific viral determinants for recognition of these inhibitors have not been defined. Herein, we have selected virus mutants in the presence of human SAP and identified specific residues in the receptor-binding pocket of the viral HA which are critical for recognition and therefore susceptibility to the antiviral activities of SAP. Given the widespread expression of α(2,6)-linked sialic acid in the human respiratory tract, we propose that SAP may act as an effective receptor mimic to limit IAV infection of airway epithelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation.
- Author
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Inforzato, Antonio, Reading, Patrick C., Barbati, Elisa, Bottazzi, Barbara, Garlanda, Cecilia, and Mantovani, Alberto
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PENTRAXINS ,GLYCOSYLATION ,IMMUNITY ,INFLAMMATION ,PATHOGENIC microorganisms ,MOLECULES ,INFLUENZA viruses - Abstract
Innate immunity represents the first line of defense 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 recognize pathogen-associated molecular patterns 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. The human PTX3 protein contains a single N-glycosylation site that is fully occupied by complex type oligosaccharides, mainly fucosylated and sialylated biantennary glycans. Glycosylation has been implicated in a number of PTX3 activities, including neutralization of influenza viruses, modulation of the complement system, and attenuation of leukocyte recruitment. Therefore, this post translational modification might act as a fine tuner of PTX3 functions in native immunity and inflammation. Here we review the studies on PTX3, with emphasis on the glycan-dependent mechanisms underlying pathogen recognition and crosstalk with other components of the innate immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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32. The "sweet" side of a long pentraxin: how glycosylation affects PTX3 functions in innate immunity and inflammation.
- Author
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Inforzato, Antonio, Reading, Patrick C., Barbati, Elisa, Bottazzi, Barbara, Garlanda, Cecilia, and Mantovani, Alberto
- Subjects
CYTOLOGICAL research ,PENTRAXINS ,GLYCOSYLATION ,IMMUNITY ,IMMUNOGLOBULINS ,PATHOGENIC microorganisms - Abstract
Innate immunity represents the first line of defense 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 recognize pathogen-associated molecular patterns 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. The human PTX3 protein contains a single N-glycosylation site that is fully occupied by complex type oligosaccharides, mainly fucosylated and sialylated biantennary glycans. Glycosylation has been implicated in a number of PTX3 activities, including neutralization of influenza viruses, modulation of the complement system, and attenuation of leukocyte recruitment. Therefore, this post translational modification might act as a fine tuner of PTX3 functions in native immunity and inflammation. Here we review the studies on PTX3, with emphasis on the glycan-dependent mechanisms underlying pathogen recognition and crosstalk with other components of the innate immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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33. Influence of Pentraxin 3 (PTX3) Genetic Variants on Myocardial Infarction Risk and PTX3 Plasma Levels.
- Author
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Barbati, Elisa, Specchia, Claudia, Villella, Massimo, Rossi, Marco Luciano, Barlera, Simona, Bottazzi, Barbara, Crociati, Luisa, d'Arienzo, Carmela, Fanelli, Raffaele, Garlanda, Cecilia, Gori, Francesca, Mango, Ruggiero, Mantovani, Alberto, Merla, Giuseppe, Nicolis, Enrico B., Pietri, Silvia, Presbitero, Patrizia, Sudo, Yukio, Villella, Alessandro, and Franzosi, Maria Grazia
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PENTRAXINS ,IMMUNE system ,MYOCARDIAL infarction ,GENETIC polymorphisms ,DENDRITIC cells - Abstract
PTX3 is a long pentraxin of the innate immune system produced by different cell types (mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells) at the inflammatory site. It appears to have a cardiovascular protective function by acting on the immune-inflammatory balance in the cardiovascular system. PTX3 plasma concentration is an independent predictor of mortality in patients with acute myocardial infarction (AMI) but the influence of PTX3 genetic variants on PTX3 plasma concentration has been investigated very little and there is no information on the association between PTX3 variations and AMI. Subjects of European origin (3245, 1751 AMI survivors and 1494 controls) were genotyped for three common PTX3 polymorphisms (SNPs) (rs2305619, rs3816527, rs1840680). Genotype and allele frequencies of the three SNPs and the haplotype frequencies were compared for the two groups. None of the genotypes, alleles or haplotypes were significantly associated with the risk of AMI. However, analysis adjusted for age and sex indicated that the three PTX3 SNPs and the corresponding haplotypes were significantly associated with different PTX3 plasma levels. There was also a significant association between PTX3 plasma concentrations and the risk of all-cause mortality at three years in AMI patients (OR 1.10, 95% CI: 1.01-1.20, p = 0.02). Our study showed that PTX3 plasma levels are influenced by three PTX3 polymorphisms. Genetically determined high PTX3 levels do not influence the risk of AMI, suggesting that the PTX3 concentration itself is unlikely to be even a modest causal factor for AMI. Analysis also confirmed that PTX3 is a prognostic marker after AMI. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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34. Pentraxin-3 in chronic heart failure: the CORONA and GISSI-HF trials.
- Author
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Latini, Roberto, Gullestad, Lars, Masson, Serge, Nymo, Ståle Haugset, Ueland, Thor, Cuccovillo, Ivan, Vårdal, Mari, Bottazzi, Barbara, Mantovani, Alberto, Lucci, Donata, Masuda, Nobuhito, Sudo, Yukio, Wikstrand, John, Tognoni, Gianni, Aukrust, Pål, and Tavazzi, Luigi
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PENTRAXINS ,HEART failure patients ,CHRONIC diseases ,NATURAL immunity ,INFLAMMATION ,DISEASE progression ,STATINS (Cardiovascular agents) ,PHARMACODYNAMICS - Abstract
Aims Pentraxin-3 (PTX3) is a component of the humoral arm of innate immunity which can regulate inflammatory processes. Since the role of inflammation in the progression of chronic heart failure (HF) is debated, we investigated the prognostic value of PTX3 and the effect of a statin in two large populations of patients with HF. Methods and results Plasma levels of PTX3 were measured at randomization and after 3 months in 1457 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and 1233 patients enrolled in the GISSI-Heart Failure trial (GISSI-HF). The relationships between baseline PTX3 levels or their changes over time and mortality were evaluated with multivariable Cox proportional hazard models including clinical factors, high sensitivity C-reactive protein (hsCRP), and N-terminal pro brain natriuretic peptide (NT-proBNP). PTX3 concentration [median (Q1–Q3) = 5.34 (3.55–7.64) ng/mL, n = 2690] was higher in females, in older patients, and those with lower body mass index. Baseline elevated PTX3 was associated with a higher risk of all-cause mortality [759 events, hazard ratio (HR) for 1 SD increase 1.20, 95% confidence interval (CI) 1.12–1.30, P < 0.0001], cardiovascular mortality (587 events, HR 1.27, 95% CI 1.17–1.38, P < 0.0001), or hospitalization for worsening HF (720 events, HR 1.21, 95% CI 1.12–1.30, P < 0.0001), and marginally improved discrimination. Three-month changes in PTX3 were associated with fatal events after adjustment for hsCRP or NT-proBNP. Rosuvastatin lowered hsCRP levels but significantly raised PTX3. Conclusion In two independent clinical trials that enrolled patients with chronic HF, PTX3 was consistently associated with outcomes. The opposite effects of a statin on hsCRP and PTX3 call for further investigation. Trial registration NCT00336336 (GISSI-HF), NCT00206310 (CORONA). [ABSTRACT FROM AUTHOR]
- Published
- 2012
35. Pentraxin-3 as a Marker of Advanced Atherosclerosis Results from the Bruneck, ARMY and ARFY Studies.
- Author
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Knoflach, Michael, Kiechl, Stefan, Mantovani, Alberto, Cuccovillo, Ivan, Bottazzi, Barbara, Qingbo Xu, Qingzhong Xiao, Arno Gasperi, Mayr, Agnes, Kehrer, Marlene, Willeit, Johann, and Wick, Georg
- Subjects
ATHEROSCLEROSIS ,PENTRAXINS ,C-reactive protein ,INFLAMMATION ,CAROTID artery ,CARDIOVASCULAR diseases - Abstract
Objective: Pentraxins like C-reactive protein are key components of the innate immune system. Recently, pentraxin-3 (PTX3) has been proposed to be a specific marker of vascular inflammation, yet its association with atherosclerosis is still unclear. Methods and Results: PTX3 serum levels were measured in three independent studies of 132 young men (ARMY Study), 205 young women (ARFY Study) and 562 individuals 55 to 94 years old (Bruneck Study). In contrast to C-reactive protein, PTX3 showed little relationships with classic vascular risk factors and pro-inflammatory conditions. In the population based Bruneck Study, PTX3 level was independently associated with prevalent cardiovascular diseases (multivariable odds ratio [95%CI] 3.09 [1.65-5.79]; P,0.001). Moreover, PTX3 level correlated with the severity of carotid and femoral atherosclerosis and was highest in individuals with multiple vascular territories affected. In contrast, there was no association with elevated intima-media thickness, a precursor lesion of atherosclerosis, in any of the three populations investigated. Conclusions: Level of PTX3 is independently associated with atherosclerosis and manifest cardiovascular disease but not early vessel pathology. Unlike C-reactive protein, PTX3 is not a component of the classic acute phase response (systemic inflammation) but appears to be more specific for vascular inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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36. The long pentraxin PTX3: from innate immunity to ischemic heart disorders
- Author
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Bottazzi, Barbara, Peri, Giuseppe, Garlanda, Cecilia, Doni, Andrea, Baviera, Stefania, Latini, Roberto, Maggioni, Aldo, and Mantovani, Alberto
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IMMUNITY , *CORONARY disease , *HEART diseases , *C-reactive protein , *GLOBULINS - Abstract
The long pentraxin PTX3 was originally identified (cDNA and genomic, mouse and human) as an IL-1 inducible gene in endothelial cells. PTX3 is a prototypic long pentraxin consisting of a C-terminal pentraxin domain (with similarity to C-reactive protein, CRP, and serum amyloid P (SAP) component), coupled to an unrelated N terminal portion. Unlike CRP, produced in the liver, it is induced by inflammatory signals mainly in endothelial cells and macrophages. Recent data in gene-targeted mice show that PTX3 is a unique, soluble pattern recognition receptor playing a non-redundant role in innate immunity and female fertility. PTX3 is produced in atherosclerotic lesions and levels increase in ischemic heart disorders. Recent results on the prognostic significance of PTX3 in acute myocardial infarction (AMI) are encouraging. [Copyright &y& Elsevier]
- Published
- 2004
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37. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization.
- Author
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Salustri, Antonietta, Garlanda, Cecilia, Hirsch, Emilio, De Acetis, Marika, Maccagno, Alessia, Bottazzi, Barbara, Doni, Andrea, Bastone, Antonio, Mantovani, Giovanna, Peccoz, Paolo Beck, Salvatori, Giovanni, Mahoney, David J., Day, Anthony J., Siracusa, Gregorio, Romani, Luigina, and Mantovani, Alberto
- Subjects
NATURAL immunity ,CELLS ,TRYPSIN inhibitors ,TUMOR necrosis factors ,EXTRACELLULAR matrix - Abstract
PTX3 is a prototypic long pentraxin that plays a non-redundant role in innate immunity against selected pathogens and in female fertility. Here, we report that the infertility of Ptx3
-/- mice is associated with severe abnormalities of the cumulus oophorus and failure of in vivo, but not in vitro, oocyte fertilization. PTX3 is produced by mouse cumulus cells during cumulus expansion and localizes in the matrix. PTX3 is expressed in the human cumulus oophorus as well. Cumuli from Ptx3-/- mice synthesize normal amounts of hyaluronan (HA), but are unable to organize it in a stable matrix. Exogenous PTX3 restores a normal cumulus phenotype. Incorporation in the matrix of inter-α-trypsin inhibitor is normal in Ptx3-/- cumuli. PTX3 does not interact directly with HA, but it binds the cumulus matrix hyaladherin tumor necrosis factor a-induced protein 6 (TNFAIP6, also known as TSG6) and thereby may form multimolecular complexes that can cross-link HA chains. Thus, PTX3 is a structural constituent of the cumulus oophorus extracellular matrix essential for female fertility. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
38. Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration.
- Author
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Stravalaci, Matteo, Davi, Francesca, Parente, Raffaella, Gobbi, Marco, Bottazzi, Barbara, Mantovani, Alberto, Day, Anthony J., Clark, Simon J., Romano, Mario R., and Inforzato, Antonio
- Subjects
RETINAL degeneration ,COMPLEMENT activation ,COMPLEMENT factor H ,COMPLEMENT inhibition ,RHODOPSIN ,PHARMACOLOGY - Abstract
Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a "hot spot" for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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39. Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin.
- Author
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Fossati, Giuliana, Pozzi, Davide, Canzi, Alice, Mirabella, Filippo, Valentino, Sonia, Morini, Raffaella, Ghirardini, Elsa, Filipello, Fabia, Moretti, Milena, Gotti, Cecilia, Annis, Douglas S, Mosher, Deane F, Garlanda, Cecilia, Bottazzi, Barbara, Taraboletti, Giulia, Mantovani, Alberto, Matteoli, Michela, and Menna, Elisabetta
- Subjects
PENTRAXINS ,AMPA receptors ,CENTRAL nervous system ,ASTROCYTES ,THROMBOSPONDINS - Abstract
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. Synopsis: Pentraxin 3 (PTX3) is a soluble innate immunity molecule that plays a key role in recognition and binding of microbial moieties and complement components. PTX3 also interacts with extracellular matrix components and contributes to the structural three‐dimensional organization of the extracellular matrix. PTX3 is expressed and released by glial cells in the developing rodent brain.PTX3 promotes formation and maturation of excitatory synapses by enhancing the synaptic recruitment of AMPARs.PTX3 regulates synaptic AMPARs through the remodeling of ECM surrounding excitatory synapses.Glial‐derived thrombospondin‐1 (TSP1) regulates PTX3 activity through direct interaction. Murine astrocytes release innate immunity‐associated PTX3 at early postnatal stages, where it plays a key role in the functional maturation of excitatory synapses by promoting AMPAR recruitment at synapses. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
40. The yin-yang of long pentraxin PTX3 in inflammation and immunity.
- Author
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Daigo, Kenji, Mantovani, Alberto, and Bottazzi, Barbara
- Subjects
- *
PENTRAXINS , *INFLAMMATION , *IMMUNITY , *C-terminal residues , *AMINO acid sequence , *C-reactive protein , *PATHOLOGICAL physiology - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
41. Pentraxin 3, a novel cardiovascular biomarker, is expressed in aortic specimens of patients with coronary artery disease with and without rheumatoid arthritis.
- Author
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Hollan, Ivana, Nebuloni, Manuela, Bottazzi, Barbara, Mikkelsen, Knut, Førre, Øystein T., Almdahl, Sven Martin, Mantovani, Alberto, Fagerland, Morten Wang, Aukrust, Pål, and Meroni, Pier Luigi
- Subjects
- *
PENTRAXINS , *BIOMARKERS , *GENE expression , *AORTIC valve diseases , *CORONARY heart disease treatment , *RHEUMATOID arthritis treatment , *HISTOCHEMISTRY - Abstract
Abstract: Background: The aims were to evaluate the presence and extent of pentraxin 3 depositions in specimens from the outer layers of the aorta and from the internal thoracic artery of patients with coronary artery disease with and without rheumatoid arthritis and to search for relationships between pentraxin 3 and vascular inflammation. Methods: Using histochemistry and immunohistochemistry, we examined biopsies from the aortic adventitia and from the internal thoracic artery (both with adjacent perivascular tissue), removed during coronary artery bypass grafting in 19 rheumatoid arthritis and 20 non-rheumatoid-arthritis patients, for presence/extent of pentraxin 3 depositions, inflammatory cell infiltrates, and fibrosis. Results: In the aorta, pentraxin 3 deposition occurred in all specimens, mostly at sites with inflammatory cell infiltrates or fibrosis, and their extent was related to the extent of inflammatory cell infiltrates (rho=0.43, 95% confidence interval: 0.13–0.66, P=.007). The extent of pentraxin 3 and inflammatory cell infiltrates in the aorta was similar in rheumatoid arthritis and non-rheumatoid-arthritis patients, but rheumatoid arthritis patients had more fibrosis and a lower proportion of T-cells in inflammatory cell infiltrates. In the internal thoracic artery, pentraxin 3 occurred only in 36% patients, and inflammatory cell infiltrates and fibrosis occurred in none. Conclusions: Pentraxin 3 depositions in the outer aortic layers are common and are related to the local inflammation. On the other hand, they occur less frequently in the internal thoracic artery, i.e., a vessel highly resistant to atherosclerosis. Rheumatoid arthritis patients had more pronounced fibrosis in the aortic specimens and a different leukocytic response than non-rheumatoid-arthritis patients. In theory, pentraxin 3 might modulate the inflammatory process involved in the pathogenesis of cardiovascular disease and represent a target for new therapies. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
42. Interactions of the humoral pattern recognition molecule PTX3 with the complement system
- Author
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Doni, Andrea, Garlanda, Cecilia, Bottazzi, Barbara, Meri, Seppo, Garred, Peter, and Mantovani, Alberto
- Subjects
- *
PATTERN recognition systems , *COMPLEMENT (Immunology) , *NATURAL immunity , *PENTRAXINS , *LECTINS , *CARRIER proteins - Abstract
Abstract: The innate immune system comprises a cellular and a humoral arm. The long pentraxin PTX3 is a fluid phase pattern recognition molecule, which acts as an essential component of the humoral arm of innate immunity. PTX3 has antibody-like properties including interactions with complement components. PTX3 interacts with C1q, ficolin-1 and ficolin-2 as well as mannose-binding lectin, recognition molecules in the classical and lectin complement pathways. The formation of these heterocomplexes results in cooperative pathogen recognition and complement activation. Interactions with C4b binding protein and factor H, the principal regulators of the classical, lectin and alternative complement pathways, show that PTX3 also may have a major influence on the regulation of the complement system. The complex interaction of PTX3 with the complement system at different levels has broad implications for host defence and regulation of inflammation. [Copyright &y& Elsevier]
- Published
- 2012
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43. PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis.
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Bozza, Silvia, Campo, Silvia, Arseni, Brunilde, Inforzato, Antonio, Ragnar, Lindstedt, Bottazzi, Barbara, Mantovani, Alberto, Moretti, Silvia, Oikonomous, Vasileios, De Santis, Rita, Carvalho, Agostinho, Salvatori, Giovanni, and Romani, Luigina
- Subjects
- *
ASPERGILLOSIS treatment , *PENTRAXINS , *TOLL-like receptors , *INTERFERON inducers , *INTERLEUKIN-1 receptors , *ASPERGILLUS fumigatus , *CELLULAR signal transduction - Abstract
The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with FcγRs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated signaling. Similar to Tlr4-/- mice, Md2-/- mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2-/- mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2-competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-ß-dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-ß-mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
44. Immune characterization of long pentraxin 3 in pigs infected with influenza virus.
- Author
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Crisci, Elisa, Fraile, Lorenzo, Valentino, Sonia, Martínez-Guinó, Laura, Bottazzi, Barbara, Mantovani, Alberto, and Montoya, Maria
- Subjects
- *
IMMUNE system , *PENTRAXINS , *SWINE diseases , *INFLUENZA viruses , *PATTERN recognition systems , *GENE expression , *DENDRITIC cells - Abstract
Abstract: Long pentraxin 3 (PTX3) is a conserved pattern-recognition secreted protein and a host-defence-related component of the humoral innate immune system. The aim of the present study was to characterize swine PTX3 (SwPTX3) protein expression in influenza virus infected pigs. First, we performed in silico studies to evaluate the cross-reactivity of PTX3 human antibodies against SwPTX3. Secondly, we used in vitro analysis to detect SwPTX3 presence in swine bone marrow dendritic cells (SwBMDC) upon stimulation with different agents by Western blot and immunofluorescence. Finally, the levels of SwPTX3 were assessed in experimental infection of pigs with different strains of influenza virus. This is a novel study where the expression of SwPTX3 was evaluated in the context of a pathogen infection. The initial characterization of SwPTX3 in influenza virus infected pigs contributes to understand the role of PTX proteins in the immune response. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
45. Prototypic Long Pentraxin PTX3 Is Present in Breast Milk, Spreads in Tissues, and Protects Neonate Mice from Pseudomonas aeruginosa Lung Infection.
- Author
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Jaillon, Sébastien, Mancuso, Giuseppe, Hamon, Yveline, Beauvillain, Céline, Cotici, Viorica, Midiri, Angelina, Bottazzi, Barbara, Nebuloni, Manuela, Garlanda, Cecilia, Frémaux, Isabelle, Gauchat, Jean-François, Descamps, Philippe, Beninati, Concetta, Mantovani, Alberto, Jeannin, Pascale, and Delneste, Yves
- Subjects
- *
LUNG infections , *PENTRAXINS , *BREAST milk , *PSEUDOMONAS aeruginosa infections , *DISEASE susceptibility , *LABORATORY mice , *PREVENTION , *THERAPEUTICS - Abstract
Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b+ milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates' health. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
46. PTX3 as a paradigm for the interaction of pentraxins with the Complement system.
- Author
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Inforzato, Antonio, Doni, Andrea, Barajon, Isabella, Leone, Roberto, Garlanda, Cecilia, Bottazzi, Barbara, and Mantovani, Alberto
- Subjects
- *
PENTRAXINS , *COMPLEMENT (Immunology) , *MANNOSE-binding lectins , *IMMUNOGENETICS , *MOLECULAR recognition , *PROTEINS - Abstract
Highlights: [•] Pentraxins interact with Complement components. [•] PTX3 interaction with ficolins and MBL amplifies repertoire of microbial recognition. [•] PTX3 interactions with Complement regulators prevent exaggerated activation. [•] Modulation of Complement activity by pentraxins has implications for host defense. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
47. Complement factor H and the long pentraxin PTX3 cooperate in the immune response to Aspergillus fumigatus.
- Author
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Inforzato, Antonio, Parente, Raffaella, Petroni, Francesca, Sironi, Marina, Leone, Roberto, Valentino, Sonia, Bottazzi, Barbara, and Mantovani, Alberto
- Subjects
- *
COMPLEMENT factor H , *PENTRAXINS , *IMMUNE response , *ASPERGILLUS fumigatus , *ASPERGILLOSIS , *IMMUNOCOMPROMISED patients - Published
- 2017
- Full Text
- View/download PDF
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