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


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.
From the Department of Medicine (L.M.B., M.K., K.T., J.E.F.) and Quantitative Health Sciences (E.M.), University of Massachusetts Medical School, Worcester, MA; Department of Medicine (E.L., M.K., E.O.W., C.D.K., C.A.G., E.J.B.), Section of Infectious Disease (C.A.G.), and Department of Microbiology (C.A.G.), Boston University School of Medicine, MA; NHLBI and Boston University's Framingham Heart Institute, Framingham, MA (M.G.L., E.J.B.); and Department of Mathematics and Statistics, Boston University, MA (M.G.L.).
Lea M
LM
Beaulieu
Elaine
E
Lin
Eric
E
Mick
Milka
M
Koupenova
Ellen O
EO
Weinberg
Carolyn D
CD
Kramer
Caroline A
CA
Genco
Kahraman
K
Tanriverdi
Martin G
MG
Larson
Emelia J
EJ
Benjamin
Jane E
JE
Freedman
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D016866:Bacteroidaceae Infections / Q000097:blood / Q000473:pathology; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology; D004041:Dietary Fats / Q000633:toxicity; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000097:blood* / Q000150:complications / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D016966:Porphyromonas gingivalis; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004041:Dietary Fats; C508590:IL1R1 protein, human; C583355:IL1R1 protein, mouse; D007093:Imidazoles; D053583:Interleukin-1beta; D016328:NF-kappa B; D011725:Pyridines; D053573:Receptors, Interleukin-1 Type I; D003094:Collagen; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; C093642:SB 203580
IL1R1 protein, human; blood platelets; diet, high-fat; infection; megakaryocytes