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Characterization of mice with a platelet-specific deletion of the adapter molecule ADAP.
Rudolph, Jochen Michael Guttek, Karina Weitz, Gabriele Meinke, Clara Antonia Kliche, Stefanie Reinhold, Dirk Schraven, Burkhart Reinhold, Annegret
Rudolph, Jochen Michael
Guttek, Karina
Weitz, Gabriele
Meinke, Clara Antonia
Kliche, Stefanie
Reinhold, Dirk
Schraven, Burkhart
Reinhold, Annegret
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2019-03-04
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Abstract
The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knock-out mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knock-out mice (ADAPfl/fl PF4-Cretg). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even after stimulation conditions. ADAPfl/fl PF4-Cretg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and TGF-β1. In vitro, platelets from these mice revealed reduced P-selectin expression, lower TGF-β1 release, diminished integrin αIIbβ3 activation and decreased fibrinogen binding after stimulation with podoplanin, the ligand of the C-type lectin-like receptor-2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of PLCγ2 and Erk1/2. Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-β1 early after T cell transfer improved EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.
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en
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1098-5549
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Attribution-NonCommercial-ShareAlike 4.0 International