The Characterization of Monoclonal Antibodies to Mouse TLT-1 Suggests That TLT-1 Plays a Role in Wound Healing

Manfredi, Barbara; Morales-Ortíz, Jessica; Díaz-Díaz, Lymarie M; Hernández-Matias, Liz; Barreto-Vázquez, Delmaliz; Menéndez-Pérez, Javier; Rodríguez-Cordero, J Alejandro; Villalobos‐Santos, Juan C.; Santiago-Rivera, Edgardo; Rivera-Dompenciel, Adriana; Lozada-Delgado, Eunice L; Kuchibhotla, Madhavi; Carrasquillo-Carrión, Kelvin; Roche-Lima, Abiel; Washington, A. Valance

doi:10.1089/mab.2017.0063

Cited by 6 publications

(3 citation statements)

References 17 publications

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“…Treml1 −/− platelets demonstrated ~2X less pβ3 Y773 at 5 minutes and less over the 20-minute period ( p =0.03; figure 1g). Addition of an anti-TLT-1 monoclonal antibody(Manfredi et al, 2018) yielded a significant decrease in pβ3 Y773 accumulation and supports the idea that TLT-1 stabilizes αIIbβ3 on the platelet surface by mediating integrin outside in signaling.…”

Section: Results and Discussion:-supporting

confidence: 65%

Controls Early Thrombus Formation and Stability by Facilitating Αiibβ3 Outside-in Signaling in Mice.

Morales-Ortíz

Reyes

Ocatavio

et al. 2018

IJAR

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Platelets regulate inflammation as well as hemostasis. Inflammatory insults often induce hemostatic function through mechanisms that are not always understood. The triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is an abundantly expressed platelet receptor and its deletion leads to hemorrhage and edema after lipopolysaccharide and TNF-α treatment. To define a role for TLT-1 in immune derived bleeding we used a CXCL-2 mediated local inflammatory reaction in the vessels of the cremaster muscle of treml1−/− and wild type mice. Our whole mount immunofluorescent staining of the cremaster muscle demonstrated a 50% reduction in clot size and increased extravasation of plasma molecules in treml1−/− mice compared to wild type. We demonstrate that the decreased clotting in treml1−/− mice is associated with a 2X reduction in integrin β3 phosphorylation on residue Y773 after platelet activation, which is consistent with treml1−/− mice displaying reduced outside-in signaling and smaller thrombi. We further substantiate TLT-1’s role in the regulation of immune derived bleeding using the reverse arthus reaction and demonstrate TLT-1’s role in thrombosis using the thromboplastin initiated and collagen/epinephrine models of pulmonary embolism. Thus, the data presented here demonstrate that TLT-1 regulates early clot formation though the stabilization of αIIbβ3 outside-in signaling.

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Section: Results and Discussion:-supporting

confidence: 65%

Controls Early Thrombus Formation and Stability by Facilitating Αiibβ3 Outside-in Signaling in Mice.

Morales-Ortíz

Reyes

Ocatavio

et al. 2018

IJAR

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“…To evaluate the possible therapeutic potential of TLT-1, we used voldemort, a polyclonal anti-TLT-1 antibody with reactivity to amino acids 122 to 139 of TLT-1 produced in our laboratory. 25 When we inhibited TLT-1 by adding anti-TLT-1 polyclonal antibodies to the transmigration assays, there was a 3.2 times reduction in transmigration (P 5 .035) and an associated 47% increase in the abundance of platelet-neutrophil conjugates over assays with control antibodies, supporting a concept that TLT-1 is necessary for platelet release of the neutrophil (P 5 .0065, n 5 4; Figure 3H,J,L). Conversely, the addition of sTLT-1 reduced the platelet-neutrophil conjugate phenotype of treml1 2/2 neutrophils by 2.8 times (P 5 .0035) and increased the proportion of neutrophils that transmigrated as single units by 54.6% (P 5 .046; Figure 3I,K,M).…”

Section: In Vitro Evaluation Of Tlt-1 Effects On Neutrophils and Neutmentioning

confidence: 68%

Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model

Morales-Ortíz

Deal

Reyes

et al. 2018

Blood

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Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)–like transcript 1 (TLT-1) is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (P < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor (P < .0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition, and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73 ± 24.75% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (P ≤ .001) and tissue damage by 25% (P ≤ .001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS.

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“…ITGB3 (integrin subunit beta 3) and ITGA2B (integrin subunit alpha 2 beta; both component chains of the heteromeric, platelet-specific integrin αIIbβ3), have also been the focus of intense interest in sepsis (255)(256)(257)(258). TREML1 is an αgranule-localized platelet factor, which functions in aggregation, bleeding, and inflammation (259)(260)(261), of which soluble forms are of interest in disease control (262,263). TGFB1I1 (Hic-5) is a transforming growth factor β1 (TGF-β1) -induced matrix protein, involved in matrix formation and cell adhesion (264)(265)(266)(267)(268)(269)(270)(271)(272)(273).…”

Section: Myl9mentioning

confidence: 99%

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

et al. 2020

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Sepsis is defined as dysregulated host response caused by systemic infection, leading to organ failure. It is a life-threatening condition, often requiring admission to an intensive care unit (ICU). The causative agents and processes involved are multifactorial but are characterized by an overarching inflammatory response, sharing elements in common with severe inflammatory response syndrome (SIRS) of non-infectious origin. Sepsis presents with a range of pathophysiological and genetic features which make clinical differentiation from SIRS very challenging. This may reflect a poor understanding of the key gene inter-activities and/or pathway associations underlying these disease processes. Improved understanding is critical for early differential recognition of sepsis and SIRS and to improve patient management and clinical outcomes. Judicious selection of gene biomarkers suitable for development of diagnostic tests/testing could make differentiation of sepsis and SIRS feasible. Here we describe a methodologic framework for the identification and validation of biomarkers in SIRS, sepsis and septic shock patients, using a 2-tier gene screening, artificial neural network (ANN) data mining technique, using previously published gene expression datasets. Eight key hub markers have been identified which may delineate distinct, core disease processes and which show potential for informing underlying immunological and pathological processes and thus patient stratification and treatment. These do not show sufficient fold change differences between the different disease states to be useful as primary diagnostic biomarkers, but are instrumental in identifying candidate pathways and other associated biomarkers for further exploration.

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The Characterization of Monoclonal Antibodies to Mouse TLT-1 Suggests That TLT-1 Plays a Role in Wound Healing

Cited by 6 publications

References 17 publications

Controls Early Thrombus Formation and Stability by Facilitating Αiibβ3 Outside-in Signaling in Mice.

Controls Early Thrombus Formation and Stability by Facilitating Αiibβ3 Outside-in Signaling in Mice.

Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

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