Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice

Abstract

Leukocyte adhesion to P-selectin on activated platelets and endothelial cells induces shedding of the P-selectin ectodomain into the circulation. Plasma soluble P-selectin (sP-selectin) is elevated threefold to fourfold in patients with cardiovascular disease. Circulating sP-selectin is thought to trigger signaling in leukocytes that directly contributes to inflammation and thrombosis. However, sP-selectin likely circulates as a monomer, and in vitro studies suggest that sP-selectin must dimerize to induce signaling in leukocytes. To address this discrepancy, we expressed the entire ectodomain of mouse P-selectin as a monomer (sP-selectin) or as a disulfide-linked dimer fused to the Fc portion of mouse immunoglobulin G (sP-selectin-Fc). Dimeric sP-selectin-Fc, but not monomeric sP-selectin, triggered integrin-dependent adhesion of mouse leukocytes in vitro. Antibody-induced oligomerization of sP-selectin or sP-selectin-Fc was required to trigger formation of neutrophil extracellular traps. Injecting sP-selectin-Fc, but not sP-selectin, into mice augmented integrin-dependent adhesion of neutrophils in venules, generated tissue factor-bearing microparticles, shortened plasma-clotting times, and increased thrombus frequency in the inferior vena cava. Furthermore, transgenic mice that overexpressed monomeric sP-selectin did not exhibit increased inflammation or thrombosis. We conclude that elevated plasma sP-selectin is a consequence rather than a cause of cardiovascular disease.

Mitochondria in cancer metabolism, an organelle whose time has come?

“…In a more recent study presented as an abstract venetoclax was combined with the hypomethylating agent azacytidine for elderly patients with AML. This small study revealed very encouraging response rates with an 85% remission rate [66]. The final results of this study are pending at this time.…”

Secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis

“…Among the biomarkers of inflammation and cardiovascular disease, soluble P-selectin was the only one to significantly correlated with S-SMase. Circulating soluble P-selectin is thought to trigger signaling in leucocytes that directly contributes to inflammation and thrombosis, and it is elevated in patients with cardiovascular diseases [12]. Soluble P-selectin has also been found to correlate with disease activity in RA patients with thrombocytosis [13].…”

“…Patients with RA and control subjects participated in studies of inflammation and cardiovascular disease at Vanderbilt University Medical Center. Patients with RA met previously described inclusion and exclusion criteria and were studied between 2009 and 2011 as part of the baseline visit of a study of the anti-inflammatory effects of pioglitazone [12]. The control subjects were studied between 2013 and 2014 as part of a cardiac magnetic resonance imaging study, unpublished.…”

Selectins and chemokines use shared and distinct signals to activate β2 integrins in neutrophils

“…The data represent the mean 6 SEM from 5 experiments, with 5 mice in each experimental group. 38 Because monomeric soluble P-selectin does not signal, 48 we used oligomeric P-selectin isolated from human platelets. As control for mAbs KIM127 and MEM148, we used mAb IB4, which binds equivalently to nonactivated and activated b2 integrins.…”