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

Abstract

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.

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…P-selectin has at least two waves of aggregation at the cell surface: one at 10 min and the other at 12 h after endotoxic or oxidative stress [144]. In addition, neutrophils rolling on P-selectin secrete the cytokine oncostatin M. The released oncostatin M can also trigger signals through glycoprotein 130 (gp 130)-containing receptors on ECs that result in a further clustered P-selectin and markedly enhanced adhesive function [143]. P-selectin also interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed by GPIIb/IIIa-fibrinogen bridges [145].…”

“…Early inflammatory mediators like histamine, thrombin, hypoxia or phorbol esters can stimulate EC in vitro, causing endothelial damage or endotheliopathy. These agonists mobilize P-selectin to the apical membranes of EC where P-selectin initiates the rolling adhesion of flowing neutrophils [143]. Although not the focus of this review, the interactions of the rolling of neutrophils, P-selectin and the endothelial cells are shown in a simplified diagram, Figure 9.…”

COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…These agonists mobilize P-selectin to the apical membranes of EC where it initiates the rolling adhesion of flowing neutrophils [137].…”

“…In addition, neutrophils rolling on P-selectin secrete the cytokine oncostatin M . The released oncostatin M can also triggered signals through glycoprotein 130 (gp130)-containing receptors on ECs that, resulting in a further clustered P-selectin and markedly enhanced its adhesive function [137]. P-selectin also interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed by GPIIb/IIIa-fibrinogen bridges [139].…”

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…However, the sustained activation of inflammatory pathways due to the action of the OMS promotes the progression of heart failure [ 180 , 188 , 189 ]. Setiadi et al pointed out the possible relationship of OSM with thrombosis, highlighting that the endothelial signalling of OSM released by neutrophils increases P-selectin-dependent inflammation, increasing the recruitment of neutrophils and monocytes during the early stages of inflammation and thrombosis [ 190 ].…”