Article

P-selectin primes leukocyte integrin activation during inflammation

Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Nature Immunology (Impact Factor: 24.97). 09/2007; 8(8):882-92. DOI: 10.1038/ni1491
Source: PubMed

ABSTRACT Selectins mediate leukocyte rolling and prime leukocytes for integrin-mediated leukocyte adhesion. However, neither the in vivo importance of nor the signaling pathway by which selectin-mediated integrin activation occurs has been determined. We report here that P-selectin-deficient mice manifested impaired leukocyte adhesion, which was 'rescued' by soluble P-selectin. Mechanistically, the cytoplasmic domain of P-selectin glycoprotein ligand 1 formed a constitutive complex with Nef-associated factor 1. After binding of P-selectin, Src kinases phosphorylated Nef-associated factor 1, which recruited the phosphoinositide-3-OH kinase p85-p110delta heterodimer and resulted in activation of leukocyte integrins. Inhibition of this signal-transduction pathway diminished the adhesion of leukocytes to capillary venules and suppressed peritoneal infiltration of leukocytes. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by P-selectin glycoprotein ligand 1.

Download full-text

Full-text

Available from: Tao Xu, Mar 18, 2014
1 Follower
 · 
96 Views
  • Source
    • "Thus, activated platelet interaction with PSGL-1 on monocytes promotes an inflammatory reaction by COX-2/mPGES-1 expression and this effect may contribute to plaque destabilization [122]. In addition to P-selectin- PSGL1 (platelet-leukocyte) interaction [123], RAGE-Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression [33] [124]. Strikingly, leukocyte adhesion in acutely inflamed venules almost completely disappears in the absence of RAGE [125]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the context of plaque progression, platelet hyperactivity associated with hyperlipidemia contributes to the development of a pro-thrombotic state. In this context, it has been demonstrated that advanced glycation end products (AGEs) significantly increases platelet activation and receptor for AGEs (RAGE) expression at the platelet surface membrane. In addition to AGEs, other ligands (S100, HMGB1 and amyloid β, among others) of RAGE have raised particular attention in platelet activation. Therefore, in this article we describe platelet hyperactivity by AGEs via RAGE-independent and RAGE-dependent pathways.
    Thrombosis Research 11/2013; 133(3). DOI:10.1016/j.thromres.2013.11.007 · 2.43 Impact Factor
  • Source
    • "Blocking either the receptor or the ligand with a monoclonal Ab completely inhibited PMN rolling on platelets [38]. Ligation of PSGL-1 induces signaling pathways that prime β 2 integrin on leukocytes [26] [40]. Despite these potentiating events, primary adhesion and arrest of leukocytes on developing thrombi requires culminating activation of their β 2 integrin [60] by additional external stimuli mostly charged by platelet-associated PAF and CXC chemokines [43] (Fig. 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Platelet activation is known to be associated with the release of a vast array of chemokines and proinflammatory lipids which induce pleiotropic effects on a wide variety of tissues and cells, including leukocytes. During thrombosis, the recruitment of leukocytes to activated platelets is considered an important step which not only links thrombosis to inflammatory responses but may also enhance procoagulant state. This phenomenon is highly regulated and influenced by precise mutual interactions between the cells at site of vascular injury and thrombi formation. Platelet-leukocyte interaction involves a variety of mediators including adhesion molecules, chemokines and chemoattractant molecules, shed proteins, various proinflammatory lipids and other materials. The current review addresses the detailed mechanisms underlying platelet-leukocyte crosstalk. This includes their adhesive interactions, transcellular metabolisms, induced tissue factor activity and neutrophil extracellular traps formation as well as the impacts of these phenomena in modulation of the proinflammatory and procoagulant functions in a reciprocal manner that enhances the physiological responses.
    Thrombosis Research 12/2012; 131(3). DOI:10.1016/j.thromres.2012.11.028 · 2.43 Impact Factor
  • Source
    • "j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h ro m re s L-selectin in leukocytes (as it was believed earlier) as well as in trophoblasts (as found out later) [5]. The pathophysiologic factors can activate endothelial cells, blood platelets and leukocytes, which results in selectin expression on the cell membrane, followed by intracellular interaction (in the case of complications a cascade of cellular events can be observed, including tethering and rolling of leukocytes on the vascular wall, their subsequent firm adhesion or transmigration [6] ). As for the lack of E-selectin in the amniotic fluid, we may assume, based on the data concerning the selectin sources, (a) that the amnion cells, lining the interior of the amnion sac and having a direct contact with the amniotic fluid, do not synthesize E-selectin (as it would be released to the fluid), and (b) that this substance is also missing in the nasopharyngeal/bronchial secretions and urine excretion of the fetus that pass to the amniotic fluid [7]. "
    Thrombosis Research 01/2011; 127(1):60-1. DOI:10.1016/j.thromres.2010.05.021 · 2.43 Impact Factor
Show more