TY - JOUR
T1 - PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcRγ to induce slow leukocyte rolling
AU - Zarbock, Alexander
AU - Abram, Clare L.
AU - Hundt, Matthias
AU - Altman, Amnon
AU - Lowell, Clifford A.
AU - Ley, Klaus
PY - 2008/9/29
Y1 - 2008/9/29
N2 - E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the β2 integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of Gαi-protein-coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin-mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr-/- or hck-/- lyn-/- fgr-/- mice. Neutrophils from Tyrobp-/- Fcrg-/- mice lacking both DAP12 and FcR-/- were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp-/- Fcrg-/- mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRγ is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.
AB - E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the β2 integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of Gαi-protein-coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin-mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr-/- or hck-/- lyn-/- fgr-/- mice. Neutrophils from Tyrobp-/- Fcrg-/- mice lacking both DAP12 and FcR-/- were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp-/- Fcrg-/- mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRγ is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.
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U2 - 10.1084/jem.20072660
DO - 10.1084/jem.20072660
M3 - Article
C2 - 18794338
AN - SCOPUS:53349171447
SN - 0022-1007
VL - 205
SP - 2339
EP - 2347
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -