Papers by Yeny Martinez de la Torre
Journal of Reproductive Immunology, Sep 1, 2009
Increased inflammation in mice deficient for the chemokine decoy receptor D6
European Journal of Immunology, May 1, 2005
Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and posit... more Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and positioning under homeostatic and inflammatory conditions. D6 is a promiscuous 7‐transmembrane‐domain receptor expressed on lymphatic vessels which recognizes most inflammatory, but not homeostatic, CC chemokines. In vitro experiments demonstrated that D6 is unable to signal after ligand engagement, and it is structurally adapted to sustain rapid and efficient ligand internalization and degradation. These unique functional properties lead to the hypothesis that D6 may be involved in the control of inflammation by acting as a decoy and scavenger receptor for inflammatory chemokines. Consistent with this hypothesis, here we report that D6–/– mice showed an anticipated and exacerbated inflammatory response in a model of skin inflammation. Moreover, the absence of D6 resulted in increase cellularity and inflammatory‐chemokine levels in draining lymph nodes. Thus, D6 is a decoy receptor structurally adapted and strategically located to tune tissue inflammation and control transfer of inflammatory chemokines to draining lymph nodes.
Proteomics is the study of expressed proteins which emerged to complement genomic research. The m... more Proteomics is the study of expressed proteins which emerged to complement genomic research. The major advantage of proteomics is it investigates directly the functional molecules (proteins), not the source code. Proteomics holds the promise of providing more direct insight into true mechanisms of human diseases. Because placenta is a key pathophysiological participant in several major obstetrical syndromes such as preterm labor and preeclampsia (PE), identification of relevant biomarkers can profoundly impact on prediction of fetal outcome and treatment efficacy. For the last several years our group pioneered a complex series of experiments aimed to better understand the pathophysiology of preterm labor and PE. We first concentrated in understanding the relationships between histological chorioamnionitis, funisitis and presence in amniotic fluid of proteomic biomarkers characteristic of inflammation (DEFENSIN-1 and-2, and CALGRANULIN C and A). Amniotic fluid profiles were generated from 139 women with singleton pregnancies admitted with signs or symptoms of preterm birth and enrolled prospectively. Proteomic analysis of the amniotic fluid provides an opportunity for early recognition of histological chorioamnionitis and targeted treatment of the fetus, in utero, prior to clinical manifestation of the disease. We further performed comprehensive proteomics profiling of the urine of women with hypertensive disorders during pregnancy (n¼272), including women with severe or superimposed PE. We found that a panel of proteomic biomarkers, non-random fragments of SERPINA-1 and ALBUMIN, can accurately predict and diagnose PE and discriminate this condition from other hypertensive proteinuric diseases in pregnancy. De-novo sequencing in MS/MS mode followed by validation experiments in the urine and placenta identified presence and localization of the biomarkers. In the placenta SERPINA-1 was sequestered within the fetal space. Our results provided insight into a novel pathological mechanism of PE which may offer new therapeutic opportunities in the future.
Novel players in female fertility: The long pentraxin PTX3 and the chemokine decoy receptor D6
The foetal-maternal interaction results in the induction of a local inflammatory response and a s... more The foetal-maternal interaction results in the induction of a local inflammatory response and a state of systemic inflammation. Several factors are involved in successful embryonic implantation, including hormones, growth factors, cytokines, chemokines, adhesion molecules, extracellular matrix components, and matrix-degrading enzymes. The enriched cytokine milieu associated to implantation is likely to control trophoblast migration and differentiation, leukocyte influx and activation, complement activation, as well as angiogenic and angiostatic processes in the implantation site. Finally, these mediators play a key role in tuning the immune responses to protect the foetus from infections as well as from maternal rejection. Here, the role of two new players involved in regulating inflammation at the maternal-foetal interface will be discussed: the long pentraxin PTX3 and the decoy receptor for inflammatory chemokines D6.
D6 as a Decoy and Scavenger Receptor for Inflammatory CC Chemokines in the Skin
Handbook of Systemic Autoimmune Diseases, 2006
Publisher Summary This chapter review recent studies, which have shed new light on the specificit... more Publisher Summary This chapter review recent studies, which have shed new light on the specificity, mode of action and actual function in the skin of one silent receptor, the D6 molecule, which behaves as a decoy and scavenger receptor for inflammatory CC chemokines. The chemokine system includes at least three seemingly silent receptors, Duffy antigen receptor for chemokines (DARC), D6, and CCX CKR. These molecules are structurally characterized by the lack of a canonical residue in the second transmembrane domain (TM) domain and of a canonical DRY motif in the second intracellular loop. There is strong evidence for DARC and D6 that these receptors do not activate conventional signaling responses. DARC has most likely a dual function, acting as a mechanism that facilitates transfer of chemokines across vascular endothelium and as a chemokine-buffering system under different circumstances. In vitro and in vivo evidence, including gene-targeted mice, is consistent with the view that D6 is a bona fide decoy receptor and scavenger for inflammatory CC chemokines. D6 is strategically located on lymphatic endothelial cells in the skin and other organs. Its ligand-independent shuttling from the plasma membrane to endocytic compartments where chemokines are targeted to degradation represents a unicum for 7 TM receptors. Thus, D6 is a genuine decoy and scavenger for inflammatory CC chemokines, uniquely adapted and located to tame inflammation in the skin and for draining lymph nodes.
The long pentraxin PTX3 in vascular pathology
Vascular Pharmacology, 2006
Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition proteins ... more Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition 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 in response to proinflammatory signals and Toll-like receptor (TLR) engagement. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes, acting as a predecessor of antibodies. 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 non-redundant component of the humoral arm of innate immunity and involved in tuning inflammation, in matrix deposition and female fertility.
Proceedings of the National Academy of Sciences, 2007
Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a p... more Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6 −/− pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.
Journal of Reproductive Immunology, 2009
Increased inflammation in mice deficient for the chemokine decoy receptor D6
European Journal of Immunology, 2005
Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and posit... more Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and positioning under homeostatic and inflammatory conditions. D6 is a promiscuous 7‐transmembrane‐domain receptor expressed on lymphatic vessels which recognizes most inflammatory, but not homeostatic, CC chemokines. In vitro experiments demonstrated that D6 is unable to signal after ligand engagement, and it is structurally adapted to sustain rapid and efficient ligand internalization and degradation. These unique functional properties lead to the hypothesis that D6 may be involved in the control of inflammation by acting as a decoy and scavenger receptor for inflammatory chemokines. Consistent with this hypothesis, here we report that D6–/– mice showed an anticipated and exacerbated inflammatory response in a model of skin inflammation. Moreover, the absence of D6 resulted in increase cellularity and inflammatory‐chemokine levels in draining lymph nodes. Thus, D6 is a decoy receptor structural...
Cytokine & Growth Factor Reviews, 2005
The chemokine system includes at least three ''silent'' receptors, DARC, D6 and CCX CKR, with dis... more The chemokine system includes at least three ''silent'' receptors, DARC, D6 and CCX CKR, with distinct specificity and tissue distribution. D6 binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation. In vitro and in vivo evidence, including results with gene-targeted mice, is consistent with the view that D6 acts as a decoy and scavenger for inflammatory CC chemokines. Thus, D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium to dampen inflammation in tissues and draining lymph nodes.
Pentraxins: Multifunctional proteins at the interface of innate immunity and inflammation
BioFactors, 2009
Pentraxins are a family of multimeric pattern recognition proteins highly conserved in evolution.... more Pentraxins are a family of multimeric pattern recognition proteins highly conserved in evolution. On the basis of the primary structure of the protomer, pentraxins are divided into two groups: short pentraxins and long pentraxins. C reactive protein, the first pattern recognition receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver in response to IL‐6. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll‐like receptor (TLR) engagement and inflammatory cytokines. Through interaction with several ligands, including selected pathogens and apoptotic cells, pentraxins play a role in complement activation, pathogen recognition and apoptotic cell clearance. In addition, PTX3 is involved in the deposition of extracellular matrix and female fertility. Unlike the classic short pentraxins CRP and ...
The chemoattractant decoy receptor D6 as a negative regulator of inflammatory responses
Biochemical Society Transactions, 2006
Other than signalling receptors sustaining leucocyte recruitment during inflammatory reactions, t... more Other than signalling receptors sustaining leucocyte recruitment during inflammatory reactions, the chemokine system includes ‘silent’ receptors with distinct specificity and tissue distribution. The best-characterized molecule of this subgroup is the CC chemokine receptor D6, which binds most inflammatory CC chemokines and targets them to degradation via constitutive ligand-independent internalization. Structure–function analysis and recent results with gene-targeted animals indicate that D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium and placenta to dampen inflammation in tissues and draining lymph nodes.
American Journal of Reproductive Immunology, 2007
responses by radioimmunoassay and plasma cytokine concentration by cytometric bead array. Results... more responses by radioimmunoassay and plasma cytokine concentration by cytometric bead array. Results: TNFalpha concentration was increased by lipopolysaccharide in all groups but was significantly less in the pregnant vs virgin mice. Hypothalamic gene (nur77 and CRH) mRNA expression responses were also significantly lower in pregnant mice. However, ACTH and corticosterone secretory responses were significantly greater in pregnancy compared to virgins. Conclusion: Although cytokine and hypothalamic responses to immune stress are reduced in early pregnancy hormone secretion is enhanced. Thus, elevated stress hormones may play a role in stressinduced abortion.
The Journal of Immunology, 2010
Pentraxins (PTXs) are a superfamily of multifunctional conserved proteins, some of which are comp... more Pentraxins (PTXs) are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of Abs. They are divided into short (C-reactive protein and serum amyloid P component) and long pentraxins (PTX3 and neuronal pentraxins). Based on a search for pentraxin domain-containing sequences in databases, a phylogenetic analysis of the pentraxin family from mammals to arthropods was conducted. This effort resulted in the identification of a new long pentraxin (PTX4) conserved from mammals to lower vertebrates, which clusters alone in phylogenetic analysis. The results indicated that the pentraxins consist of five clusters: short pentraxins, which can be found in chordate and arthropods; neuronal pentraxins; the prototypic long pentraxin PTX3, which originated very early at the divergence of the vertebrates; the Drosophila pentraxin-like protein B6; and the long pentraxin PTX4 discovered in this study....
Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization
Proceedings of the National Academy of Sciences, 2012
Activated macrophages are described as classically activated or M1 type and alternatively activat... more Activated macrophages are described as classically activated or M1 type and alternatively activated or M2 type, depending on their response to proinflammatory stimuli and the expression of genetic markers including iNOS, arginase1, Ym1, and Fizz1. Here we report that Akt kinases differentially contribute to macrophage polarization, with Akt1 ablation giving rise to an M1 and Akt2 ablation resulting in an M2 phenotype. Accordingly, Akt2 −/− mice were more resistant to LPS-induced endotoxin shock and to dextran sulfate sodium (DSS)-induced colitis than wild-type mice, whereas Akt1 −/− mice were more sensitive. Cell depletion and reconstitution experiments in a DSS-induced colitis model confirmed that the effect was macrophage-dependent. Gene-silencing studies showed that the M2 phenotype of Akt2 −/− macrophages was cell autonomous. The microRNA miR-155, whose expression was repressed in naive and in LPS-stimulated Akt2 −/− macrophages, and its target C/EBPβ appear to play a key role i...
Journal of Autoimmunity, 2012
β 2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and aff... more β 2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of β2GPI and inhibits β2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT.
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Papers by Yeny Martinez de la Torre