Role of TIR8/SIGIRR in regulating TLR and IL-1R like-dependent platelet activation

TIR8, or single Ig IL-1R-related molecule, SIGIRR, is a member of the IL-1R like (ILR) family, which acts as negative regulator of TLR and ILR signalling, playing non-redundant roles in tuning inflammatory responses in different pathological conditions. Platelets express functional TLRs, which are involved in sepsisinduced thrombocytopenia, binding of bacteria, neutrophil extracellular trap production and platelet activation via P-selectin and active GPaIIIbII upregulation. In addition, IL-1RI has been shown in platelets. We investigated the expression of TIR8/SIGIRR and other ILR regulated by TIR8 in platelets, and defined the potential involvement of TIR8/SIGIRR in TLR- and ILR-dependent platelet activation. We confirmed IL-1RI expression and showed for the first time TIR8/SIGIRR, IL-18R and IL-33R expression in human and murine platelets and megakaryocytes. Functional studies showed that stimulation with TLR and ILR ligands (LPS, IL-1βand IL-18) induced upregulation of P-selectin and active GPIIbIIIa and calcium mobilization. Platelet TIR8/SIGIRR expression was downregulated upon LPS stimulation or in patients with Systemic Inflammatory Response Syndrome compared to healthy donors. Finally, functional studies showed that Tir8-deficiency in mice was associated to platelet hyperactivity in basal conditions and upon stimulation with LPS, IL-18 and IL-1β, as demonstrated by increased P-selectin and active GPaIIIbII upregulation, calcium mobilization and neutrophil/platelet aggregation. Thus, TIR8/SIGIRR is a regulator of platelet activation in inflammatory conditions induced by TLR and ILR family ligands. The modulation of TIR8/SIGIRR expression in platelets in severe inflammatory conditions suggests that it might represent a novel diagnostic or therapeutic target in prothrombotic conditions associated to inflammatory diseases.