Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response
Mihnea P. Dragomir, … , Sai-Ching Yeung, George A. Calin
Mihnea P. Dragomir, … , Sai-Ching Yeung, George A. Calin
Published June 1, 2023
Citation Information: J Clin Invest. 2023;133(14):e158348. https://doi.org/10.1172/JCI158348.
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Research Article Immunology Infectious disease

Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response

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.

Authors

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, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P. Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S. Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A. Calin

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Figure 2

miR-93-5p expression in 2 baboon models of sepsis and in long-term sepsis survivors.

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miR-93-5p expression in 2 baboon models of sepsis and in long-term sepsi...
(A) Left panel: Plasma levels of miR-93-5p at different time points in an E. coli (Gram–) baboon sepsis model (n = 6). Purple bar represents the expression of miR-93-5p before death in baboons that died late after inoculation; red bar represents the expression of miR-93-5p before death in baboons that died early after inoculation. Middle panel: miR-93-5p dynamics in E. coli–inoculated baboons that died late (n = 3). Right panel: miR-93-5p dynamics in E. coli–inoculated baboons that died early (n = 3). (B) Left panel: Plasma levels of miR-93-5p at different time points in an S. aureus (Gram+) baboon sepsis model (n = 5). Purple bar represents the expression of miR-93-5p before death in baboons that died late after inoculation; red bar represents the expression of miR-93-5p before death in baboons that died early after inoculation. Middle panel: miR-93-5p dynamics in S. aureus–inoculated baboons that died late (n = 3). Right panel: miR-93-5p dynamics in baboons S. aureus–inoculated baboons that died early (n = 2). Expression of (C) miR-K12-12* and (D) miR-93-5p in whole blood from long-term survivors of sepsis (n = 23) at 3 different time points: day 0 = shortly after sepsis diagnosis, day 1 = 1 day after diagnosis, and day 7 = 7 days after sepsis diagnosis. The relative expression level was normalized to U6. Data are presented as the mean ± SD. ***P < 0.001 and ****P < 0.0001, by Friedman’s test. (E) Correlation between miR-93-5p levels in plasma and SOPED score (n = 59). (F) Correlation between miR-93-5p levels in plasma and the ALC (n = 48). Data were evaluated by Pearson’s correlation test (E and F).