Cellular and extracellular miRNAs are blood compartment-specific diagnostic targets for detection and survival prediction in sepsis

Marlene Reithmair 1,*, Dominik Buschmann 1,2 , Melanie Märte 3 , Benedikt Kirchner 2 , Daniel Hagl 3,4 , Ines Kaufmann 4 , Martina Pfob 1 , Alexander Chouker 3 , Ortrud Steinlein 1 , Michael W. Pfaffl 2 , Gustav Schelling 3
1 Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Munich, Germany
2 Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University Munich, Germany
3 Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University, Munich, Germany
4 Department of Anaesthesiology, Neuperlach Hospital, City Hospitals of Munich, Munich, Germany

Background: Septic shock is a common medical condition with a mortality approaching 50% where early diagnosis and treatment is of particular importance for patient survival. Novel biomark- ers that serve as prompt indicators of sepsis are urgently needed. High-throughput technologies assessing circulating microRNAs represent an important tool for biomarker identification but the blood-compartment specificity of these miRNAs has not yet been investigated.
Methods: We characterized miRNA profiles from serum exo- somes, total serum and blood cells (leukocytes, erythrocytes, platelets) of sepsis patients (n = 22) by next-generation sequenc- ing and RT-qPCR and established differences in miRNA expression between blood compartments. In-silico analysis was used to iden- tify compartment-specific signaling functions of differentially regulated miRNAs in sepsis-relevant pathways.
Results: In septic shock, a total of 77 and 103 miRNAs were down- and upregulated, respectively. A majority of these regu- lated miRNAs (14 in serum, 32 in exosomes, 73 in blood cells) had not been previously associated with sepsis. We found a dis- tinctly compartment-specific regulation of miRNAs between sepsis patients and healthy volunteers. Blood cellular miR-199b-5p was identified as a potential early indicator for sepsis and septic shock. miR-125b-5p and miR-26b-5p were uniquely regulated in exo- somes and serum, respectively, while one miRNA (miR-27b-3p) was present in all three compartments. In-silico analysis identified crucial signaling pathways such as LPS-stimulated toll-like receptor and HIF-1a-signaling regulated by exosome derived miRNAs.
Conclusions: The expression of sepsis-associated miRNAs is compartment-specific. Exosome-derived miRNAs contribute sig- nificant information regarding sepsis diagnosis and survival prediction and could serve as newly-identified targets for the devel- opment of novel sepsis biomarkers.

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