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Immunoreceptor tyrosine‐based activation motif (ITAM)‐containing adapters DAP12 and FcRγ required for E‐selectin mediated slow rolling
Author(s) -
Zarbock Alexander,
Lowell Clifford A.,
Ley Klaus
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1071.1
Subject(s) - syk , signal transducing adaptor protein , microbiology and biotechnology , p selectin , inflammation , phosphorylation , tyrosine , receptor , immunoreceptor tyrosine based activation motif , cremaster muscle , signal transduction , chemistry , biology , tyrosine kinase , immunology , platelet activation , in vivo , platelet , biochemistry
E‐selectin binding to PSGL‐1 can induce slow rolling by activating the β 2 ‐integrin LFA‐1 through a spleen tyrosine kinase (Syk)‐dependent pathway. Immunoreceptor tyrosine‐base activation motifs (ITAMs) are required for Syk activation downstream from B‐cell and Fc receptors. Neutrophils express two ITAM‐containing adaptor molecules, FcRγ and DAP12. To test their role in E‐selectin‐mediated slow rolling, we investigated Fcrg −/− and Tyrobp −/− as well as Fcrg −/− Tyrobp −/− mice by intravital microscopy of the cremaster muscle and in autoperfused flow chambers. In wild‐type mice, rolling velocity on E‐selectin was 2.2 μm/s. Adding ICAM‐1 to the substrate reduced rolling velocity to 1.0 μm/s. This velocity reduction was partially blunted in Fcrg −/− or Tyrobp −/− and completely eliminated in Fcrg −/− Tyrobp −/− mice, suggesting that the ITAM domains of DAP12 and FcRγ are partially redundant for E‐mediated slow rolling. Lethally irradiated WT mice reconstituted with bone marrow from Fcrg −/− Tyrobp −/− mice and WT mice revealed that leukocytes from Fcrg −/− Tyrobp −/− mice showed markedly elevated rolling velocities in TNF‐α‐induced inflammation in vivo. Phosphorylation of Syk and p38 MAPK following E‐selectin engagement was completely abolished in Fcrg −/− Tyrobp −/− mice. The physiologic importance of our findings is shown by near complete inhibition of neutrophil recruitment into the inflamed peritoneal cavity of Fcrg −/− Tyrobp −/− treated with pertussis toxin to block Gα i signaling. These data show that the DAP12 and FcRγ provide the ITAM domains necessary for downstream signaling and slow rolling following E‐selectin engagement.