Citation

LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro-IL-1 RNA. Although the IL-1R type 1 (IL-1R1) receptor for IL-1 shares downstream components with the TLR4 receptor, platelets are not known to express IL-1R1, nor are they known to respond to this cytokine. We show by flow cytometry and Western blotting that platelets express IL-1R1, and that IL-1 and IL-1 stimulate heteronuclear I-1 splicing and translation of the newly made mRNA in platelets. Platelets also respond to the IL-1 they make, which is exclusively associated with shed microparticles. Specific blockade of IL-1R1 with IL-1R antagonist suppressed platelet stimulation by IL-1, so IL-1 stimulates its own synthesis in an autocrine signaling loop. Strikingly, IL-1R antagonist inhibition, pharmacologic or genetic suppression of pro-IL-1 processing to active cytokine by caspase-1, or blockade of de novo protein synthesis also blocked LPS-induced IL-1 mRNA production. Robust stimulation of platelets by LPS therefore also required IL-1 amplification. Activated platelets made IL-1 in vivo as IL-1 rapidly accumulated in occluded murine carotid arteries by posttranscriptional RNA splicing unique to platelets. We conclude that IL-1 is a platelet agonist, that IL-1 acts through an autocrine stimulatory loop, that an IL-1 autocrine loop is required to amplify platelet activation by LPS, and that platelets immobilized in occlusive thrombi are activated over time to produce IL-1. IL-1 is a new platelet agonist that promotes its own synthesis, connecting thrombosis with immunity.