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Reduced miR-26b Expression in Megakaryocytes and Platelets Contributes to Elevated Level of Platelet Activation
Bernadett Szilágyi1,2, Zsolt Fejes1,2, Szilárd Póliska3
1Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary.
Abstract:
In sepsis, platelets may become activated via toll-like receptors (TLRs), causing microvascular thrombosis. Megakaryocytes (MKs) also express these receptors; thus, severe infection may modulate thrombopoiesis. To explore the relevance of altered miRNAs in platelet activation upon sepsis, we first investigated sepsis-induced miRNA expression in platelets of septic patients. The effect of abnormal Dicer level on miRNA expression was also evaluated. miRNAs were profiled in septic vs. normal platelets using TaqMan Open Array. We validated platelet miR-26b with its target SELP (P-selectin) mRNA levels and correlated them with clinical outcomes. The impact of sepsis on MK transcriptome was analyzed in MEG-01 cells after lipopolysaccharide (LPS) treatment by RNA-seq. Sepsis-reduced miR-26b was further studied using Dicer1 siRNA and calpain inhibition in MEG-01 cells. Out of 390 platelet miRNAs detected, there were 121 significantly decreased, and 61 upregulated in sepsis vs. controls. Septic platelets showed attenuated miR-26b, which were associated with disease severity and mortality. SELP mRNA level was elevated in sepsis, especially in platelets with increased mean platelet volume, causing higher P-selectin expression. Downregulation of Dicer1 generated lower miR-26b with higher SELP mRNA, while calpeptin restored miR-26b in MEG-01 cells. In conclusion, decreased miR-26b in MKs and platelets contributes to an increased level of platelet activation status in sepsis.
Insights
Sepsis reduces miR-26b levels in platelets and megakaryocytes, increasing platelet activation and thrombosis risk. This decrease in miR-26b is linked to disease severity and mortality in septic patients.
Area of Science:
- Hematology
- Molecular Biology
- Immunology
Background:
- Sepsis can activate platelets via toll-like receptors (TLRs), leading to microvascular thrombosis.
- Megakaryocytes (MKs), the precursors of platelets, also express TLRs, suggesting infection may affect thrombopoiesis.
Purpose of the Study:
- To investigate sepsis-induced microRNA (miRNA) expression changes in platelets.
- To explore the role of altered miRNA levels, specifically miR-26b, in platelet activation during sepsis.
- To evaluate the impact of Dicer levels on miRNA expression in sepsis.
Main Methods:
- miRNA profiling in platelets from septic patients and healthy controls using TaqMan Open Array.
- Validation of miR-26b and its target SELP (P-selectin) mRNA levels.
- RNA-sequencing of MEG-01 cells treated with lipopolysaccharide (LPS) to analyze MK transcriptome.
- Experimental manipulation of Dicer1 and calpain in MEG-01 cells to study miR-26b regulation.
Main Results:
- 121 miRNAs were significantly decreased and 61 upregulated in septic platelets compared to controls.
- Septic platelets exhibited reduced miR-26b levels, correlating with disease severity and mortality.
- Elevated SELP mRNA levels and increased P-selectin expression were observed in septic platelets.
- Dicer1 downregulation led to decreased miR-26b and increased SELP mRNA, while calpeptin treatment restored miR-26b.
Conclusions:
- Decreased miR-26b in megakaryocytes and platelets is a key factor in heightened platelet activation during sepsis.
- Reduced miR-26b contributes to the pro-thrombotic state observed in sepsis.
- miR-26b may serve as a potential biomarker for sepsis severity and outcomes.
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