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

Abstract

Objective Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1β, 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, IL1β levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1β, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis. Approach and Results We found that IL1β-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, IL1β activated nuclear factor-κB and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1β, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1β increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1β 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 IL1β−/− mice. Conclusions In summary, IL1R1- and IL1β-related transcripts are elevated in the setting of obesity. IL1R1/IL1β augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.

Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

“…CD40-dependent platelet-leukocyte cross talk promoted the release of IL-1β, a major mediator of plateletinduced activation of the endothelium by inducing endothelial adhesion molecule expression (VCAM-1 and intercellular adhesion molecule-1) and cytokine production (IL-6 and IL-8). 49,50 In addition, we show that platelet CD40 has an important role in promoting endothelial activation and attracting more monocytes and neutrophils toward the site of inflammation.…”

The Growing Problem of Obesity

“…Beaulieu and colleagues reported on studies from the Framingham Heart Study subjects in whom it was shown that IL-1β-related genes in platelets were associated with increased BMI and in mice, analogous observations were made 19 . The authors showed that IL-1 receptor 1 and IL-1β mRNA transcripts, elevated in obesity, increased both mekakaryocyte and platelet functions particularly in mice treated with the periodontal pathogen, Porphyromonas gingivalis , thereby suggesting that these inflammatory factors promote a prothrombotic environment in infection and obesity 19 .…”

Leucócitos como marcadores de risco para doenças cardiovasculares na adolescência: associação com características de nascimento, situação nutricional e exames bioquímicos

“…The mean platelet volume is considered an indicator of platelet activity; its increase was demonstrated in several acute vascular events and it is associated with obesity 22. Increased platelet activation is known to trigger atherosclerosis and plays an important role in its progression.…”

“…O volume plaquetário médio é considerado um indicador da atividade plaquetária, seu aumento foi demonstrado em diversos eventos vasculares agudos e está relacionado com a obesidade 22. O aumento da ativação das plaquetas é conhecido por desencadear a aterosclerose e desempenha papel importante na sua progressão.…”