Back to Search
Start Over
CpG oligonucleotides induce acute murine thrombocytopenia dependent on toll-like receptor 9 and spleen tyrosine kinase pathways.
- Source :
-
Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Nov; Vol. 22 (11), pp. 3266-3276. Date of Electronic Publication: 2024 Aug 21. - Publication Year :
- 2024
-
Abstract
- Background: CpG oligonucleotides (ODNs) are synthetic single-stranded DNA sequences that act as immunostimulants. They have been increasingly used to treat several cancers; however, thrombocytopenia is a potential recognized side effect of some sequences.<br />Objectives: We tested the ability of 2 CpG ODNs (ODN 2395 and ISIS 120704) to induce thrombocytopenia when administered to BALB/c mice and determined mechanisms associated with thrombocytopenia.<br />Methods: BALB/c mice were prebled and then injected with titrated doses of CpG ODNs, and platelet counts were determined. The mice were treated with intravenous immunoglobulin (IVIg) or various inhibitors and antagonists of toll-like receptor 9 (TLR9) and spleen tyrosine kinase (Syk) to determine their effects on thrombocytopenia.<br />Results: Compared with saline-treated mice or mice treated with 2'-O-methoxyethyl-modified antisense ODN, both ODN 2395 and ISIS 120704 induced acute dose-dependent thrombocytopenia within 3 and 24 hours, respectively. The thrombocytopenia was associated with significant increases in plasma monocyte chemoattractant protein 1. IVIg administration significantly rescued the CpG ODN-induced thrombocytopenia, as did treatment with either a Syk inhibitor or TLR9 antagonists. In vitro, CpG ODN could activate human platelets and this correlated significantly with enhanced IVIg- and Syk-dependent phagocytosis by THP-1 monocytes.<br />Conclusion: These results suggest that CpG ODNs induce acute inflammatory-associated (IVIg-sensitive) thrombocytopenia that can be alleviated by Syk- or TLR9-blockade, and an IVIg- and Syk-dependent platelet clearance pathway appears primarily responsible for the thrombocytopenia.<br />Competing Interests: Declaration of competing interests There are no competing interests to disclose.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Female
Humans
Mice
Acute Disease
Chemokine CCL2 metabolism
Chemokine CCL2 genetics
Disease Models, Animal
Mice, Inbred BALB C
Platelet Count
Protein Kinase Inhibitors pharmacology
THP-1 Cells
Blood Platelets metabolism
Blood Platelets drug effects
Blood Platelets enzymology
Immunoglobulins, Intravenous
Oligodeoxyribonucleotides pharmacology
Signal Transduction
Syk Kinase antagonists & inhibitors
Syk Kinase metabolism
Thrombocytopenia chemically induced
Thrombocytopenia blood
Toll-Like Receptor 9 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7836
- Volume :
- 22
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of thrombosis and haemostasis : JTH
- Publication Type :
- Academic Journal
- Accession number :
- 39155024
- Full Text :
- https://doi.org/10.1016/j.jtha.2024.08.003