Interleukin 1 Receptor 1 and Interleukin 1&bgr; Regulate Megakaryocyte Maturation, Platelet Activation, and Transcript Profile During Inflammation in Mice and Humans

Objective— Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1&bgr;, are upregulated in cardiovascular disease, obesity, and infection. Previously, we reported a higher level of IL1R1 transcripts in platelets from obese individuals of the Framingham Heart Study (FHS), but its functional effect in platelets has never been described. Additionally, IL1&bgr; levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1&bgr;, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis. Approach and Results— We found that IL1&bgr;-related genes from platelets, as measured in 1819 FHS participants, were associated with increased body mass index, and a direct relationship was shown in wild-type mice fed a high-fat diet. Mechanistically, IL1&bgr; activated nuclear factor-&kgr;B and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1&bgr;, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1&bgr; increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1&bgr; increased adhesion to both collagen and fibrinogen, and heterotypic aggregation by 1.9-fold over resting. High fat diet-enhanced platelet adhesion was absent in IL1R1−/− mice. Wild-type mice infected with Porphyromonas gingivalis had circulating heterotypic aggregates (1.5-fold more than control at 24 hours and 6.2-fold more at 6 weeks) that were absent in infected IL1R1−/− and IL1&bgr;−/− mice. Conclusions— In summary, IL1R1- and IL1&bgr;-related transcripts are elevated in the setting of obesity. IL1R1/IL1&bgr; augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.

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