P-selectin primes leukocyte integrin activation during inflammation

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.

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

“…Finally, ABIN-1 contains an 'YPPM' motif, with Y552 being a target for phosphorylation by Src kinases (Fig. 1B) [28]. Whereas ABIN-1 is predominantly cytoplasmic, treatment of HeLa cells with an inhibitor of Crm-1 mediated nuclear export (leptomycin B) results in its nuclear accumulation, suggesting that ABIN-1 constitutively shuttles between the cytosol and the nucleus in a Crm-1 dependent way [16].…”

“…Finally, ABIN-1 also constitutively binds to the cytoplasmic domain of P-selectin glycoprotein ligand 1 (PSGL-1) in human neutrophils [28]. ABIN-1 becomes phosphorylated by Src kinases on Y552 upon P-selectin binding to PSGL-1, leading to the recruitment of phosphoinositide-3 kinase (PI3K) p85-p110 heterodimer and the activation of  M  2 integrinmediated leukocyte adhesion.…”

Leukocyte transendothelial migration: A local affair

“…31 Leukocytes scanned for activated platelets to interact via P-selectin glycoprotein ligand-1 (PSGL-1) resulting in clustering and activation of the b2 integrin Mac-1 that mediates neutrophil TEM. 32,33 This simultaneous interaction with activated platelets and the endothelium results in rapid neutrophil exit and the onset of inflammation. 34 Using platelets as intermediate substrates, monocytes are able to transmigrate under high shear stress varying between 20 and 40 dyn/cm.…”

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

“…Following initial tethering via P-selectin and PSGL-1, it was suggested that additional molecular interactions, involving the b2 integrin a M b 2 (Mac-1), a4b1 and VCAM-1, extracellular matrix metalloproteinase inducer, and triggering receptor expressed on myeloid cells-1 may be involved in strengthening monocyteplatelet binding (13)(14)(15)(16)(17). Although the exact contribution made by these additional molecules remains to be determined, it also was shown that the interaction with P-selectin promotes the association of PSGL-1 with the cytoskeletal proteins ezrin and moesin and the tyrosine kinase Syk (18), resulting in phosphorylation of the Src family kinases and activation of PI3K (19)(20)(21). These pathways were shown to regulate a number of important monocyte functions, including cytoskeletal rearrangement, activation of b2 integrins (16,18), the transcription of proinflammatory genes, and the induction of inflammatory cytokine and chemokine secretion (7,9,10,19,(22)(23)(24).…”