MiRNAs and Neutrophil-Related Membrane Proteins from Plasma-Derived Extracellular Vesicles for Early Prediction of Organ Dysfunction and Prognosis in Septic Patients

Abstract

Rongzong Ye,1,* Yating Wei,1,* Jingwen Li,2,* Meili Xu,1 Haiyang Xie,2 Jiahao Huang,3 Liehua Deng,3 Chaoqian Li1 1Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 2Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liehua Deng, Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, 57 People’s Ave South, Zhanjiang, Guangdong, 524000, People’s Republic of China, Email [email protected] Chaoqian Li, Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China, Email [email protected]: The pathogenesis of sepsis-induced organ dysfunction remains elusive, and the mortality remains alarmingly high. We sought to investigate the profile of extracellular vesicles (EVs)-mediated communication between plasma and polymorphonuclear neutrophils (PMNs) in sepsis, and to elucidate whether miRNAs and PMN-related membrane proteins from plasma-derived EVs (plasma-EVs) are associated with sepsis-induced organ dysfunction and prognosis.Methods: PMN-derived EVs (PMN-EVs) were isolated from the blood samples of healthy controls (N=3) and patients with septic shock (N=3) after ICU admission. We performed miRNA sequencing of the isolated EVs, followed by bioinformatic analysis. A miRNA model for comparing PMN-EVs and plasma-EVs was successfully established in the training cohort. Furthermore, miRNAs and PMN-related membrane proteins from the plasma-EV model were confirmed in the validation cohort. A logistic regression model, receiver operating characteristic (ROC) curves, and Kaplan-Meier analyses were performed to evaluate the efficiency of diagnostic and/or prognostic performance. Further, in vivo and in vitro experiments were conducted to explore the involvement of plasma-EVs in PMNs autophagy.Results: Fifty-five miRNAs from PMN-EVs differed significantly between the healthy controls and patients with septic shock. Furthermore, the plasma-EV model (six miRNAs and eight PMN-related membrane proteins) was confirmed in the validation cohort, demonstrating that miR-34a-5p, miR-503-5p, miR-4772-3p, ITGAM, MPO, and MMP9 serve as sepsis biomarkers for distinguishing lung, liver, and kidney dysfunction. Kaplan–Meier survival analysis showed that miR-34a-5p, miR-4772-3p, ITGAM, and MMP9 were potential prognostic predictors. Finally, we found that plasma-EVs from sepsis patients exert an inhibitory effect on PMNs autophagy, which can be reversed by EV inhibitors such as GW4869 and enoxaparin.Conclusion: These findings suggest that miRNAs and PMN-related membrane proteins from plasma-EVs could be valuable diagnostic tools for identifying sepsis-induced organ dysfunction and predicting prognosis, enabling proactive management of sepsis by physicians and improving the prognosis of sepsis patients.Keywords: extracellular vesicles, MicroRNAs, membrane proteins, sepsis-induced organ dysfunction, neutrophils, autophagy

Keywords

• extracellular vesicles
• micrornas
• membrane proteins
• sepsis-induced organ dysfunction
• neutrophils
• autophagy