Biology subjects

Brill, A.

Publications and source records attributed to Brill, A..

3 recordsLinked to original sources

bioRxiv2026

Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis

Background: Venous thromboembolism is increasingly recognized as a thrombo-inflammatory disease, yet the pathways linking inflammation to venous thrombus initiation remain incompletely defined. Galectin-9 (Gal-9), a {beta}-galactoside-binding lectin elevated in inflammatory disorders, has no defined role in venous thrombosis. Methods: Using plasma from patients with deep vein thrombosis (DVT), Gal-9-deficient mice, an inferior vena cava stenosis model, intravital microscopy, microfluidics, and ex vivo platelet and neutrophil assays, we assessed the functional contribution of Gal-9 to venous thrombosis. Results: Plasma Gal-9 was elevated in DVT patients, correlated with D-dimer at presentation, and declined over 3-month follow-up. Gal-9 deletion did not alter hemostasis but markedly impaired thrombus initiation, with reduced platelet and neutrophil recruitment to the vessel wall and reduced intra-thrombus neutrophil extracellular trap (NET) formation. TNF-/IFN-{gamma}-stimulated endothelial cells upregulated Gal-9 and promoted platelet adhesion and fibrin(ogen) deposition, which Gal-9 neutralization partially reversed. Under venous shear, immobilized recombinant Gal-9 potentiated platelet activation and thrombus formation, particularly alongside collagen, whereas Gal-9 inhibition suppressed these responses. Gal-9-activated platelets promoted NETosis and shifted thrombus composition toward a NET-rich inflammatory phenotype. Conclusions: Gal-9 is a previously unrecognized driver of venous thrombo-inflammation, linking vascular inflammation to platelet activation, NET formation, and thrombosis. Genetic deletion attenuated these responses in vivo, and antibody-mediated Gal-9 neutralization suppressed platelet activation and thrombus formation in vitro, identifying the Gal-9 glycan-binding pathway as a therapeutic target that disrupts thrombosis without impairing hemostasis.

immunology↗

bioRxiv2024

Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice

Sickle cell disease (SCD) leads to hemolytic anemia, vaso-occlusive crisis (VOC), hypoperfusion, and progressive organ damage. Hemin, released during hemolysis in SCD, induces platelet activation through CLEC-2, endothelial activation through TLR4, neutrophil adhesion and NETosis, all of which are regulated by spleen tyrosine kinase (Syk). In this study, we assessed neutrophil and platelet recruitment to the pulmonary, renal, splenic, and hepatic microvasculature in control and SCD mice following hemin injection and the effect of Syk inhibition on cell recruitment and organ perfusion. Compared to controls, SCD mice exhibited higher baseline neutrophil and platelet recruitment to the lungs without alterations in lung perfusion as measured by laser speckle contrast imaging. Injection of hemin increased cell recruitment to the pulmonary and renal vasculature with a concomitant reduction in organ perfusion. However, hemin injection did not change cell recruitment or organ perfusion in the spleen and liver, both of which were altered at baseline in SCD mice. Pretreatment of SCD mice with the Syk inhibitor BI-1002494 mitigated baseline and hemin-induced neutrophil and platelet adhesion in the pulmonary and renal microvasculature, with a corresponding normalization of perfusion. Syk regulates vascular integrity in the lung of SCD mice; whilst high concentrations of BI-1002494 increased bleeding, lowering drug concentrations preserved the inhibitory effect on platelet and neutrophil recruitment and lung perfusion and protected from bleeding complications. These data substantiate Syk as a mediator of vascular thrombo-inflammation and hypoperfusion in the lung and kidney of SCD and provide a rationale for pharmacological inhibition as a therapeutic strategy.

pathology↗

bioRxiv2020

CLEC-2 promotes inflammatory peritoneal macrophage emigration to draining lymph nodes during endotoxemia

Macrophage recruitment during sterile inflammation and infection is essential to clear pathogens, apoptotic cells and debris. However, persistent macrophage accumulation leads to chronic inflammation. Platelets are emerging as key modulators of the inflammatory response. Here, we identify that platelet C-type-lectin-like receptor-2 (CLEC-2) is a crucial immunomodulatory receptor through the interaction with podoplanin, upregulated on inflammatory macrophages. Mechanistically, platelet CLEC-2 upregulates the expression of podoplanin and its co-ligands CD44 and ERM proteins, leading to actin rearrangement and promotion of cell migration; this is mimicked by recombinant CLEC-2-Fc (rCLEC-2-Fc). Treatment of LPS-challenged mice with rCLEC-2-Fc induces a rapid emigration of peritoneal macrophages to mesenteric lymph nodes, through a gradient generated by the podoplanin ligand, CCL21, to prime T cells. We propose that crosslinking podoplanin using rCLEC-2-Fc is a novel, cell-specific strategy to accelerate macrophage removal from the site of inflammation, and hence promote the resolution of the inflammatory response. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/423770v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@e37acborg.highwire.dtl.DTLVardef@92a5e1org.highwire.dtl.DTLVardef@1c8832eorg.highwire.dtl.DTLVardef@11c5c97_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryPersistent macrophage accumulation in inflamed tissue leads to chronic inflammation and organ damage. Bourne et al. identify recombinant CLEC-2-Fc crosslinking podoplanin on inflammatory macrophages, as a cell-specific strategy to accelerate their emigration to draining lymph nodes, and reduce local inflammation.

immunology↗