Interleukin 1 receptor 1 and interleukin 1? regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans.

ABSTRACT: Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1?, 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? levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1?, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis.We found that IL1?-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? activated nuclear factor-?B and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1?, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1? increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1? 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?(-/-) mice.In summary, IL1R1- and IL1?-related transcripts are elevated in the setting of obesity. IL1R1/IL1? augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.

SUBMITTER: Beaulieu LM 

PROVIDER: S-EPMC4070375 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature