Achille Anselmo1, Federica Riva2, Stefania Gentile1, Cristiana Soldani1, Marialuisa Barbagallo1, Cristina Mazzon1, Francesca Feruglio1, Nadia Polentarutti1, Paolo Somma1, Pierluigi Carullo3, Claudio Angelini1, Monica Bacci1, Grazia Loredana Mendolicchio1, Antonio Voza1, Manuela Nebuloni4, Alberto Mantovani5, Cecilia Garlanda6. 1. Laboratory of Experimental Immunopathology, Humanitas Clinical and Research Center, via Manzoni 113, 20089 Rozzano, Italy. 2. Department of Animal Pathology, Faculty of Veterinary Medicine, University of Milan, Milan, Italy. 3. Laboratory of Experimental Immunopathology, Humanitas Clinical and Research Center, via Manzoni 113, 20089 Rozzano, Italy National Research Council (CNR), Institute of Genetic and Biomedical Research-UOS of Milan, Milan, Italy. 4. Pathology Unit, L. Sacco Department of Clinical Sciences, L. Sacco Hospital, University of Milan, 20157 Milan, Italy. 5. Laboratory of Experimental Immunopathology, Humanitas Clinical and Research Center, via Manzoni 113, 20089 Rozzano, Italy Humanitas University, 20089 Rozzano, Italy. 6. Laboratory of Experimental Immunopathology, Humanitas Clinical and Research Center, via Manzoni 113, 20089 Rozzano, Italy cecilia.garlanda@humanitasresearch.it.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Büin Adams; J Massimo Nunes; Martin J Page; Timothy Roberts; Jonathan Carr; Theo A Nell; Douglas B Kell; Etheresia Pretorius Journal: Front Aging Neurosci Date: 2019-08-27 Impact factor: 5.750