Abstract
LPS activates platelets through TLR4, aiding productive sepsis, with stimulated splicing and translation of stored heteronuclear pro–IL-1β 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-1β and IL-1α stimulate heteronuclear I-1β splicing and translation of the newly made mRNA in platelets. Platelets also respond to the IL-1β 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-1β stimulates its own synthesis in an autocrine signaling loop. Strikingly, IL-1R antagonist inhibition, pharmacologic or genetic suppression of pro–IL-1β processing to active cytokine by caspase-1, or blockade of de novo protein synthesis also blocked LPS-induced IL-1β mRNA production. Robust stimulation of platelets by LPS therefore also required IL-1β amplification. Activated platelets made IL-1β in vivo as IL-1β rapidly accumulated in occluded murine carotid arteries by posttranscriptional RNA splicing unique to platelets. We conclude that IL-1β is a platelet agonist, that IL-1β acts through an autocrine stimulatory loop, that an IL-1β autocrine loop is required to amplify platelet activation by LPS, and that platelets immobilized in occlusive thrombi are activated over time to produce IL-1β. IL-1 is a new platelet agonist that promotes its own synthesis, connecting thrombosis with immunity.
This article is featured in In This Issue, p.4891
Footnotes
This work was supported by National Institutes of Health Grants P50 HL081011 and 1 R01 HL092747 and by Case Western Reserve University/Cleveland Clinic Clinical and Translational Science Award UL1 RR024989 from the National Institutes of Health/National Center for Research Resources.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- hn
- heteronuclear
- IL-1R1
- IL-1R type 1
- IL-1Ra
- IL-1R antagonist
- LPB
- LPS binding protein
- TIR
- Toll/IL-1R
- TRAF
- TNFR-associated factor.
- Received February 7, 2013.
- Accepted September 5, 2013.
- Copyright © 2013 by The American Association of Immunologists, Inc.