P-selectin binding to P-selectin glycoprotein ligand-1 induces an intermediate state of alphaMbeta2 activation and acts cooperatively with extracellular stimuli to support maximal adhesion of human neutrophils.
P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and integrin alphaMbeta2 (Mac-1, CD11bCD18) are leukocyte adhesion molecules essential for innate immunity and inflammation. The interaction of PSGL-1 with P-selectin (CD62P) mediates tethering, rolling, and weak adhesion of leukocytes, during which they become sufficiently activated in situ by locally released or displayed cytokines and chemoattractants for integrin-mediated firm adhesion. However, communication between P-selectin and the integrin, whether P-selectin can trigger beta2-integrin activation, remains controversial. We found that P-selectin immunoglobulin chimera and PSGL-1 monoclonal antibodies (mAbs) increased adhesion of human neutrophils to immobilized, but not soluble, fibrinogen. This intermediate state of neutrophil adhesion was defined by moderate clustering of integrin alphaMbeta2, no increase in CBRM1/5 (a mAb specific for the activation epitope on the alphaM subunit) recognition, and no increase in surface expression of alphaMbeta2, whereas phorbol myristate acetate (PMA) induced extensive changes in these 3 parameters. Furthermore, platelet-activating factor or interleukin 8 acted in concert with P-selectin for further enhancing the activation of alphaMbeta2. We thus propose a model in which P-selectin induces an intermediate state of integrin activation and then cooperates with other extracellular stimuli to support maximal adhesion of human neutrophils.
Ma
Yan-Qing
YQ
University of Minnesota Medical School, MMC 480, 420 Delaware St SE, Minneapolis, MN 55455, USA. gengx011@umn.edu
Plow
Edward F
EF
Geng
Jian-Guo
JG
D000906:Antibodies / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D012995:Solubility; D015854:Up-Regulation
D000906:Antibodies; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D010972:Platelet Activating Factor; D005340:Fibrinogen