Expression and function in platelets of IL-1R8 (TIR8/SIGIRR), a regulatory member of the IL-1 receptor family

IL-1R8, also known as SIGIRR or TIR8, is a member of the IL-1R family that negatively regulates responses to IL-1R family members and TLRs. Here we report that IL-1R8 is expressed on human and mouse platelets at high levels. Megakaryocytes express IL-1R8 and levels increase along maturation. IL-1R8-deficient mice show normal levels of circulating platelets. Homotypic and heterotypic (platelet-neutrophil) aggregation triggered by ADP and IL-1 or LPS, respectively, was increased in IL-1R8-deficient platelets. IL-1R8-deficient mice showed increased soluble P-selectin levels and increased platelet-neutrophil aggregates after systemic LPS administration. The deficiency of IL-1R1 abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8-/- mice in vitro and in vivo, suggesting that IL-1R8-dependent negative regulation of platelet IL-1R1 has a major role in tuning platelet activation. In a mouse model of platelet-dependent thromboembolism, IL-1R8-deficient mice showed an increased frequency of blood vessel complete obstruction. IL-1R8 expression was downmodulated on platelet surface in patients with severe systemic inflammatory conditions (SIRS and sepsis) and correlated with the severity of the disease, suggesting a possible link with platelet dysfunctions associated to these conditions. These results show that platelets, which have a large repertoire of TLRs and IL-1R, express high levels of IL-1R8 that plays a non-redundant function as a regulator of thrombocyte function in vitro and in vivo.