Thromb Haemost 2018; 118(12): 2112-2125
DOI: 10.1055/s-0038-1675603
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

The Inter-Relationship of Platelets with Interleukin-1β-Mediated Inflammation in Humans

Rahajeng N. Tunjungputri
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2  Center for Tropical and Infectious Diseases (CENTRID), Dr. Kariadi Hospital, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
,
Yang Li
3  Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Philip G. de Groot
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Charles A. Dinarello
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
4  Department of Medicine, University of Colorado Denver–Aurora, Colorado, United States
,
Sanne P. Smeekens
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Martin Jaeger
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Marije Doppenberg-Oosting
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Milou Cruijsen
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Heidi Lemmers
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Helga Toenhake-Dijkstra
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Raul Aguirre-Gamboa
3  Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Vinod Kumar
3  Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Cisca Wijmenga
3  Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
5  Department of Immunology, K. G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway
,
Leo A. B. Joosten
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
6  Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
,
Mihai G. Netea
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
7  Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
,
Andre van der Ven
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
,
Quirijn de Mast
1  Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
› Author Affiliations
Funding The Human Functional Genomics Project is supported by a European Research Council (ERC) Consolidator grant (ERC 310372). R.N.T. is an awardee of the DIKTI-NESO PhD fellowship from the Ministry of Education of Indonesia. C.A.D. is supported by NIH Grant AI-15614. This study was further supported by an IN-CONTROL CVON grant (CVON2012–03) and a Netherlands Organization for Scientific Research (NWO) Spinoza prize (NWO SPI 94–212) to M.G.N; by a an ERC Advanced grant [FP/2007–2013/ERC grant 2012–322698] and an NWO Spinoza prize [NWO SPI 92–266] to C.W.; a European Union Seventh Framework Program grant (EU FP7) TANDEM project [HEALTH-F3–2012–305279] to C.W. and V.K.; and a Research Grant [2017] of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) to V.K.
Further Information

Publication History

07 June 2018

22 September 2018

Publication Date:
19 November 2018 (eFirst)

Abstract

Background Inflammation and coagulation are key processes in cardiovascular diseases (CVDs). The Canakinumab Anti-inflammatory Thrombosis Outcome Study trial affirmed the importance of inflammation in CVD by showing that inhibition of the interleukin (IL)-1β pathway prevents recurrent CVD. A bi-directional relationship exists between inflammation and coagulation, but the precise interaction of platelets and IL-1β-mediated inflammation is incompletely understood. We aimed to determine the inter-relationship between platelets and inflammation—and especially IL-1β—in a cohort of healthy volunteers.

Methods We used data from the 500-Human Functional Genomics cohort, which consists of approximately 500 Caucasian, healthy individuals. We determined associations of plasma levels of IL-1β and other inflammatory proteins with platelet number and reactivity, the association of platelet reactivity with ex vivo cytokine production as well as the impact of genetic variations through a genome-wide association study (GWAS).

Results Platelets were associated with IL-1β on different levels. First, platelet number was positively associated with plasma IL-1β concentrations (p = 8.9 × 10−9) and inversely with concentrations of α-1-anti-trypsin (p = 1.04 × 10−18), which is a known antagonist of IL-1β. Second, platelet degranulation capacity, as determined by agonist-induced P-selectin expression, was associated with ex vivo IL-1β and IL-6 production. Third, several platelet single-nucleotide polymorphisms (SNPs) were associated with cytokine production and there was a significant platelet SNP enrichment in specific biological important pathways. Finally, platelet SNPs were enriched among SNPs earlier identified in GWAS studies in blood-related diseases and immune-mediated diseases.

Conclusion This comprehensive assessment of factors associated with platelet number and reactivity reinforces the important inter-relationship of platelets and IL-1β-mediated inflammation.

Supplementary Material