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

Abstract

These results show that platelets, which have a large repertoire of TLRs and IL-1 receptors, express high levels of IL-1R8, which plays a non-redundant function as a regulator of thrombocyte activity in vitro and in vivo.

Tuning inflammation and immunity by the negative regulators IL‐1R2 and IL‐1R8

“…Hyperactivity of platelets in the absence of IL‐1R8 was dependent on IL‐1 signaling, since the phenotype was abrogated in Il1r8 −/− /Il1r1 −/− mice, in agreement with the reported role of IL‐1β in platelet activation . In addition, microflora depletion abrogated the enhanced platelet activation in IL‐1R8‐deficient mice, indicating that commensal flora‐derived TLR agonists are also involved in the phenotype . Importantly, in patients with SIRS/sepsis, which is associated with platelet dysfunction, IL‐1R8 surface expression was significantly downregulated compared to healthy controls and the downregulation reflected the severity of the disease.…”

“…Importantly, in patients with SIRS/sepsis, which is associated with platelet dysfunction, IL‐1R8 surface expression was significantly downregulated compared to healthy controls and the downregulation reflected the severity of the disease. Microparticles released from LPS‐stimulated platelets or collected from the serum of septic patients expressed higher levels of IL‐1R8 compared to controls, suggesting the shedding of the receptor in inflammatory conditions through microparticle release . These results indicate that IL‐1R8 is involved in the modulation of platelet activation, aggregation and hetero‐aggregation, both in physiological and pathological conditions in vitro and in vivo, and elucidate a novel function of IL‐1R8 in the regulation of thrombocyte function.…”

“…In particular, IL‐1R8‐deficient platelets displayed a hyperactivated phenotype in basal conditions, showing higher active α2bβ3 and P‐selectin surface expression. Upon in vitro stimulation with prothrombotic stimuli, Il1r8 −/− platelets showed enhanced aggregation amplitude and higher expression of α2bβ3 . Platelets express functional TLRs and IL‐1 family receptors (eg, IL‐1R1 and IL‐18Rα) and interestingly, IL‐1R8 deficiency in platelets was associated with increased platelet/neutrophil aggregate formation, induced by LPS, IL‐1β or IL‐18 in vitro and in a systemic LPS‐induced inflammation model in vivo .…”

“…Upon in vitro stimulation with prothrombotic stimuli, Il1r8 −/− platelets showed enhanced aggregation amplitude and higher expression of α2bβ3 . Platelets express functional TLRs and IL‐1 family receptors (eg, IL‐1R1 and IL‐18Rα) and interestingly, IL‐1R8 deficiency in platelets was associated with increased platelet/neutrophil aggregate formation, induced by LPS, IL‐1β or IL‐18 in vitro and in a systemic LPS‐induced inflammation model in vivo . Moreover, IL‐1R8‐deficient mice were more susceptible to ADP‐induced pulmonary thromboembolism, as shown by enhanced occlusion of vessels by fibrin clots and systemic levels of soluble P‐selectin.…”

“…IL‐1R8 mRNA and protein were recently detected in platelets. Downregulation of IL‐1R8 protein was observed in platelets derived from septic patients and after in vitro stimulation with LPS …”