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

IL-1R8, also known as single Ig IL-1-Related Receptor (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 murine platelets and megakaryocytes. Despite normal levels of circulating platelets IL1R8-deficient (Il1r8-/-) mice showed increased homotypic and heterotypic (platelet-neutrophil) aggregation triggered by ADP and IL-1 or LPS. Moreover IL-1R8-deficient mice showed increased soluble P-selectin levels and increased platelet-neutrophil aggregates after systemic LPS administration. Commensal flora depletion and IL-1R1 deficiency abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8-/- mice in vitro and in vivo, suggesting a key role of IL-1R8 in regulating platelet TLR and IL-1R1 function. In a mouse model of platelet-dependent pulmonary thromboembolism, IL-1R8-deficient mice showed an increased frequency of blood vessel complete obstruction. Finally, in a small cohort of patients with severe systemic inflammatory conditions, the expression of platelet IL-1R8 was dramatically abated and it was associated to platelet-derived microparticle release. Altogether our results highlight a new and efficient mechanism through which platelets, which have a large repertoire of TLRs and IL-1 receptors, regulate thrombocyte activity and identifie IL-1R8 as a novel non-redundant player in tuning platelet activation during immunity and inflammation.