Recombinant P-selectin glycoprotein ligand–1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect

Hicks, Anne E.; Nolan, Sarah L.; Ridger, Victoria; Hellewell, Paul G.; Norman, Keith E.

doi:10.1182/blood-2002-07-2329

Cited by 78 publications

(63 citation statements)

References 48 publications

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“…P-selectin is stored in endothelial cells and platelets and is rapidly mobilized to the cell surface upon stimulation. In this way, regulation of P-selectin expression rapidly alters leukocyte-endothelial interactions (6,27,28). Leukocyte rolling is also mediated by constitutively expressed L-selectin on leukocytes and transcriptionregulated E-selectin expression on endothelial cells (29).…”

Section: Discussionmentioning

confidence: 99%

C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

Scotland

Cohen

Foster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The multifaceted process of immune cell recruitment to sites of tissue injury is key to the development of an inflammatory response and involved in the pathogenesis of numerous cardiovascular disorders. We recently identified C-type natriuretic peptide (CNP) as an important endothelium-derived mediator that regulates vascular tone and protects against myocardial ischemia͞ reperfusion injury. Herein, we investigated whether CNP inhibits leukocyte recruitment and platelet aggregation and thereby exerts a potential antiinflammatory influence on the blood vessel wall. We assessed the effects of CNP on leukocyte-endothelial cell interactions in mouse mesenteric postcapillary venules in vivo in animals with high basal leukocyte activation (endothelial nitric oxide synthase knockout mice, eNOS ؊/؊ ) or under acute inflammatory conditions (induced by interleukin-1␤ or histamine). CNP suppressed basal leukocyte rolling in eNOS ؊/؊ mice in a rapid, reversible, and concentration-dependent manner. These effects of CNP were mimicked by the selective natriuretic peptide receptor-C agonist cANF 4 -23 . CNP also suppressed leukocyte rolling induced by IL-1␤ or histamine, inhibited platelet-leukocyte interactions, and prevented thrombin-induced platelet aggregation of human blood. Furthermore, analysis of human umbilical vein endothelial cells, leukocytes, and platelets revealed that CNP selectively attenuates expression of P-selectin. Thus, CNP is a modulator of acute inflammation in the blood vessel wall characterized by leukocyte and platelet activation. These antiinflammatory effects appear to be mediated, at least in part, via suppression of P-selectin expression. These observations suggest that endothelial CNP might maintain an anti-atherogenic influence on the blood vessel wall and represent a target for therapeutic intervention in inflammatory cardiovascular disorders.endothelium ͉ natriuretic peptide receptor type C ͉ atherosclerosis ͉ thrombosis L eukocyte recruitment and platelet activation at sites of tissue injury are important facets of an inflammatory response and are pivotal in the pathogenesis of a number of cardiovascular disorders including atherosclerosis and sepsis. These processes are triggered by specific inflammatory stimuli and are critically dependent on the expression of a series of adhesion molecules on the surface of leukocytes, platelets, and the vascular endothelium (1). However, this is a dynamic process; under basal (physiological) conditions, leukocyte and platelet activation is held in check by specific endothelium-derived mediators. Perhaps the most influential of these is nitric oxide (NO), which, in concert with analogous autacoids such as prostacyclin, maintains an active suppression of leukocyte and platelet activation under physiological conditions that is paramount for maintenance of blood vessel integrity and patency (2-4).The importance of NO in the prevention of leukocyte recruitment has been established by studies demonstrating increased leukocyte-endothelial interactions in animals ...

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Section: Discussionmentioning

confidence: 99%

C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

Scotland

Cohen

Foster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…25 rPSGL-Ig prevented death induced by 500 ng TNF-␣ and RB6-8C5 in 5 of 6 mice if given prior to TNF-␣ and if heparin was also applied (Figure 4). Intravital microscopy experiments revealed that these mice were also protected from microvascular arrest (not shown).…”

Section: A Role For Selectins In Reactions Induced By Tnf-␣/rb6-8c5mentioning

confidence: 95%

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

Norman

Cotter

Stewart

et al. 2003

Blood

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“…All inhibitors were applied at doses previously determined to provide maximum blockade of their respective ligands. 9,14,18,19 …”

Section: Reagentsmentioning

confidence: 99%

L- and P-Selectins Collaborate to Support Leukocyte Rolling in Vivo When High-Affinity P-Selectin-P-Selectin Glycoprotein Ligand-1 Interaction Is Inhibited

Ridger¹,

Hellewell²,

Norman³

2005

The American Journal of Pathology

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P-selectin glycoprotein ligand-1 (PSGL-1) binding to Pselectin controls early leukocyte rolling during inflammation. Interestingly, antibodies and pharmacological inhibitors (eg, rPSGL-Ig) that target the N-terminus of PSGL-1 reduce but do not abolish P-selectin-dependent leukocyte rolling in vivo whereas PSGL-1-deficient mice have almost no P-selectin-dependent rolling. We have investigated mechanisms of P-selectin-dependent, PSGL-1-independent rolling using intravital microscopy. Initially we used fluorescent microspheres to study the potential of L-selectin and the minimal selectin ligand sialyl Lewis x (sLe x ) to interact with postcapillary venules in the absence of PSGL-1. Microspheres coated with combinations of L-selectin and sLe x interacted with surgically stimulated cremaster venules in a P-selectin-dependent manner. Microspheres coated with either L-selectin or sLe x alone showed less evidence of interaction. We also investigated leukocyte rolling in the presence of PSGL-1 antibody or inhibitor (rPSGL-Ig), both of which partially inhibited P-selectin-dependent leukocyte rolling. Residual rolling was substantially inhibited by L-selectin-blocking antibody or a previously described sLe x mimetic (CGP69669A). Together these data suggest that leukocytes can continue to roll in the absence of optimal P-selectin/PSGL-1 interaction using an alternative mechanism that involves P-selectin-, L-selectin-, and sLe and present attractive targets for anti-inflammatory drugs. P-Selectin may be a good target for cardiovascular disease therapy, 2-5 although notable clinical trial disappointments 6,7 suggest that effective P-selectin inhibition may be more challenging than expected.Natural ligand mimicry is a common drug development approach. Elements of PSGL-1 required for high-affinity P-selectin recognition include a sialylated, fucosylated O-glycan and tyrosine sulfation at appropriate positions near the N-terminus. 8 Drugs mimicking one or more of these elements could theoretically inhibit P-selectin. Inhibitors based on the carbohydrate selectin ligand, sLe x , are effective, albeit in high doses, against E-selectindependent leukocyte rolling in vivo but have no measurable effect on established P-selectin-dependent rolling.

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Recombinant P-selectin glycoprotein ligand–1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect

Cited by 78 publications

References 48 publications

C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression

Combined anticoagulant and antiselectin treatments prevent lethal intravascular coagulation

L- and P-Selectins Collaborate to Support Leukocyte Rolling in Vivo When High-Affinity P-Selectin-P-Selectin Glycoprotein Ligand-1 Interaction Is Inhibited

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