Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response
Mihnea P. Dragomir, Enrique Fuentes‐Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huan-Yu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh N. Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi‐Mansat, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez‐Aguayo, Gabriel Lopez‐Berestein, Constantin Georgescu, Pinaki P. Banerjee, Rafet Başar, Ziyi Li, David Horst, Cătălin Vasilescu, Maria Teresa Sabrina Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai‐Ching J. Yeung, George A. Călin
Abstract
Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram- sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93-KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.