Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice

Ponomaryov, Tatyana; Payne, Holly; Fabritz, Larissa; Wagner, Denisa D.; Brill, Alexander

doi:10.1161/circresaha.117.311185

Cited by 73 publications

(68 citation statements)

References 51 publications

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“…Thus, we hypothesized that in JAK2-V617F-induced disease increased ICAM1 and VCAM1 expression on endothelial cells in combination with abnormal β 1 and β 2 activity may precipitate abnormal adhesion of granulocytes to endothelial cells, contributing to pathologic thrombus formation. To study the role of β 1 and β 2 integrins in this process, we employed a widely used thrombosis model of the IVC (49). We induced thrombosis in JAK2 +/+ and JAK2 +/VF mice by partial ligation of the IVC and 4 hours thereafter analyzed thrombus size and dry weight of the thrombi ( Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

Edelmann¹,

Gupta²,

Schnoeder³

et al. 2018

Journal of Clinical Investigation

104

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JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.

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Section: Resultsmentioning

confidence: 99%

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

Edelmann¹,

Gupta²,

Schnoeder³

et al. 2018

Journal of Clinical Investigation

104

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“…Modifications avoid the endothelial damage step, and further vary in their [17,46] treatment of side branches as well as the chosen spacer. One variation leaves all branches open and uses a 0.36 mm wire spacer [4], while other variations interrupt side branches and use either a 30-gauge needle spacer [3,[11][12][13][14], or a 0.26 mm wire spacer [15]. Experts in the field have noted that these modifications which avoid the endothelial damage step open a different and often variable thrombotic process in the model.…”

Section: Ligature Based Ivc Modelsmentioning

confidence: 99%

Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application

Díaz

Saha

Cooley

et al. 2019

Journal of Thrombosis and Haemostasis

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Summary Murine models are widely used valuable tools to study deep vein thrombosis (VT). Leading experts in VT research came together through the American Venous Forum to develop a consensus on maximizing the utility and application of available mouse models of VT. In this work, we provide an algorithm for model selection, with discussion of the advantages, disadvantages, and applications of the main mouse models of VT. Additionally, we provide a detailed surgical description of the models with guidelines to validate surgical technique.

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“…[42][43][44]52 Histamine released from mast cells mobilizes P-selectin to the endothelial surface of the IVC, which initiates rolling of neutrophils and monocytes. 53 Signaling through PSGL-1 and chemokine receptors on the rolling cells triggers integrindependent arrest. 42,52 Adherent neutrophils release DNA/histonerich neutrophil extracellular traps (NETs), and monocytes express tissue factor.…”

Section: Interactions Of Neutrophil-derived Osm With Gp130-containingmentioning

confidence: 99%

Endothelial signaling by neutrophil-released oncostatin M enhances P-selectin–dependent inflammation and thrombosis

et al. 2019

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In the earliest phase of inflammation, histamine and other agonists rapidly mobilize P-selectin to the apical membranes of endothelial cells, where it initiates rolling adhesion of flowing neutrophils. Clustering of P-selectin in clathrin-coated pits facilitates rolling. Inflammatory cytokines typically signal by regulating gene transcription over a period of hours. We found that neutrophils rolling on P-selectin secreted the cytokine oncostatin M (OSM). The released OSM triggered signals through glycoprotein 130 (gp130)–containing receptors on endothelial cells that, within minutes, further clustered P-selectin and markedly enhanced its adhesive function. Antibodies to OSM or gp130, deletion of the gene encoding OSM in hematopoietic cells, or conditional deletion of the gene encoding gp130 in endothelial cells inhibited neutrophil rolling on P-selectin in trauma-stimulated venules of the mouse cremaster muscle. In a mouse model of P-selectin–dependent deep vein thrombosis, deletion of OSM in hematopoietic cells or of gp130 in endothelial cells markedly inhibited adhesion of neutrophils and monocytes and the rate and extent of thrombus formation. Our results reveal a paracrine-signaling mechanism by which neutrophil-released OSM rapidly influences endothelial cell function during physiological and pathological inflammation.

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Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice

Abstract: Supplemental Digital Content is available in the text.

Cited by 73 publications

References 51 publications

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

Choosing a mouse model of venous thrombosis: a consensus assessment of utility and application

Endothelial signaling by neutrophil-released oncostatin M enhances P-selectin–dependent inflammation and thrombosis

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