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 4

Effect of anti–miR-93-5p therapy on the lymphoid and myeloid lineages.

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Effect of anti–miR-93-5p therapy on the lymphoid and myeloid lineages. (...
(A) Flow cytometric characterization of circulating lymphoid and myeloid cells in 4 different mouse groups: control (no intervention), sham-operated, CLP-induced sepsis with scrambled miRNA treatment, and CLP-induced sepsis with anti–miR-93-5p treatment. Treatment was administrated 24 hours before and 2 hours after sepsis induction. Mice were sacrificed 24 hours after surgery (sham) or CLP-induced sepsis. Control mice were sacrificed together with mice in the other 3 groups. (B) Percentage of CD4+CD44+CD62Llo/neg Tem cells (CD4+ Tem) in control mice, sham-operated mice, CLP-induced septic mice treated with scrambled miRNA, and CLP-induced septic mice treated with anti–miR-93-5p mice. (C) Percentage of CD8+ Tem cells (CD8+ Tem) in all 4 groups. (D) Percentage of CSF1R+PD-L1+ cells in the entire pool of CD11b+CSF1R+ monocytes in control mice, sham-operated mice, CLP-induced septic mice treated with scrambled miRNA, and CLP-induced septic mice treated with anti–miR-93-5p. (E) Percentage of LyChi cells in the entire pool of CD11b+CSF1R+ monocytes and of (F) LyChiPD-L1+ monocytes in control mice, sham-operated mice, CLP-induced septic mice treated with scrambled miRNA, and CLP-induced septic mice treated with anti–miR-93-5p. (G) Percentage of F4/80+MRC1+ macrophages and of (H) F4/80+PD-L1+ macrophages in all 4 experimental mouse groups. (I) Schematic representation of the effect of anti–miR-93-5p therapy on hematopoiesis during sepsis. Blue rectangles mark the cell subtypes that were significantly differentially expressed in the anti–miR-93-5p–treated group versus the scrambled miRNA–treated group after adjustment for multiple testing using the FDR. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (B–H). P values that are significant after adjustment for multiple testing using the FDR are highlighted in blue.