Expression and function of IL-1R8 (TIR8/SIGIRR): a regulatory member of the IL-1 receptor family in platelets.

Abstract

AIMS:

Platelets express functional interleukin-1 receptor-1 (IL-1R1) as well as a repertoire of toll-like receptors (TLRs) involved in platelet activation, platelet-leucocyte reciprocal activation, and immunopathology. IL-1R8, also known as single Ig IL-1-related receptor (SIGIRR) or TIR8, is a member of the IL-1R family that negatively regulates responses to IL-1R family members and TLRs. In the present study, we addressed the expression of IL-1R8 in platelets and megakaryocytes and its role in the control of platelet activation during inflammatory conditions and thromboembolism.

METHODS AND RESULTS:

Here, we show by flow cytometry analysis, western blot, confocal microscopy, and quantitative real-time polymerase chain reaction that IL-1R8 is expressed on human and mouse platelets at high levels and on megakaryocytes. IL-1R8-deficient mice show normal levels of circulating platelets. Homotypic and heterotypic (platelet-neutrophil) aggregation triggered by Adenosine DiPhosphate (ADP) and IL-1 or lipopolysaccharide (LPS) was increased in IL-1R8-deficient platelets. IL-1R8-deficient mice showed increased soluble P-selectin levels and increased platelet-neutrophil aggregates after systemic LPS administration. Commensal flora depletion and IL-1R1 deficiency abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8(-/-) mice in vitro and in vivo, suggesting a key role of IL-1R8 in regulating platelet TLR and IL-1R1 function. In a mouse model of platelet-dependent pulmonary thromboembolism induced by ADP administration, IL-1R8-deficient mice showed an increased frequency of blood vessel complete obstruction.

CONCLUSION:

These results show that platelets, which have a large repertoire of TLRs and IL-1 receptors, express high levels of IL-1R8, which plays a non-redundant function as a regulator of thrombocyte activity in vitro and in vivo.

• Authors: Achille Anselmo, Federica Riva, Stefania Gentile, Cristiana Soldani, Marialuisa Barbagallo, Cristina Mazzon, Francesca Feruglio, Nadia Polentarutti, Paolo Somma, Pierluigi Carullo, Claudio Angelini, Monica Bacci, Grazia Loredana Mendolicchio, Antonio Voza, Manuela Nebuloni, Alberto Mantovani, Cecilia Garlanda
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 111 Issue 4 Pg. 373-84 (09 2016) ISSN: 1755-3245 [Electronic] England
• PMID: 27297888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: [email protected].

Chemical References

• Interleukin-1
• Lipopolysaccharides
• Receptors, Interleukin-1
• TIR8 protein, human
• Tir8 protein, mouse
• Toll-Like Receptors

Topics

• Animals
• Blood Platelets (drug effects, metabolism)
• Disease Models, Animal
• Humans
• Immunity, Innate (drug effects)
• Inflammation (metabolism)
• Interleukin-1 (metabolism)
• Lipopolysaccharides (pharmacology)
• Mice, Transgenic
• Platelet Activation (drug effects)
• Receptors, Interleukin-1 (metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptors (metabolism)