Paired Immunoglobulin-like Receptor B Regulates Platelet Activation

Murine paired immunoglobulin-like receptors B (PIRB), as the ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), plays important roles in immune responses, neuron axonal regeneration and hematopoietic processes, but the expression and functions of PIRB in platelets remains unknown.Here, we found that PIRB and LILRB2 were expressed in mouse and human platelets, respectively. PIRB mtracellular domain deletion (PIRB-TM) mice had thrombocythemia and significantly higher proportions of megakaryocytes in bone marrow. Agonist-induced aggregation and spreading on immobilized Fg were facilitated in PIRB-TM platelets. The rate of clot retraction in platelet-rich plasma containing PIRB-TM platelets was also increased. Characterization of signaling confirmed that PIRB associated with phosphatases Shpl/2 in platelets. The phosphorylation of Shpl/2 was significantly downregulated in PIRB-TM platelets stimulated with collagen related peptide (CRP) or upon spreading. The results further revealed that the phosphorylation levels of LAT, SLP76 and PLCy2 were enhanced in PIRB-TM platelets stimulated with CRP. The phosphorylation levels of FAK Y397 and integrin 03 Y759 were also enhanced in PIRB-TM platelet spread on fibrinogen. The PIRB/LILRB2 ligand angiopoietin-like-protein 2 (Angptl2) was expressed and stored in platelet a-granules. Angptl2 inhibited agonist-induced platelet aggregation and spreading on fibrinogen.The data presented here reveal that PIRB and its ligand Angptl2 possess the antithrombotic function by suppressing collagen receptor GPVI and integrin allbp3 mediated signaling.