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.
View: Text | PDF
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

×

Figure 6

Confirmation of dysregulated miR-93-5p target genes in 2 baboon sepsis models.

Options: View larger image (or click on image) Download as PowerPoint
Confirmation of dysregulated miR-93-5p target genes in 2 baboon sepsis m...
(A) The 579 putative miR-93 target genes were overlapped with genes that showed an opposite expression (i.e., downregulation) with miR-93 levels in the 2 baboon models (gray and yellow circles). Of the 465 genes that could be assigned to a baboon ortholog (of 579 IP enriched genes; 80%), 215 and 193 were downregulated upon injection with E. coli and S. aureus, respectively. In addition, this set of genes was overlapped with predicted and validated targets of mir-93-5p as extracted from miRWalk and miRTarBase (red circle). (B) Downregulation of CD28, CD160, ZAP70, MAP3K3, and MAP4K2 upon sepsis induction in the S. aureus– and E. coli–mediated baboon models. **Q < 0.01, ***Q < 0.001, and ****Q < 0.0001, by moderate t test. Results were also adjusted to the subject effects using the LMM; significant P values after adjustment are highlighted in blue. (C) Pathway analysis of the 190 genes that were IP enriched, downregulated in either E. coli– or S. aureus–induced sepsis, or both in baboons and predicted targets of miR-93-5p. BioPlanet 2019 pathways with a P value of less than 0.01 are shown. CD28 and STAT3 are validated targets of miR-93-5p. fact., factor; interact., interaction; sign., signaling; transd., transduction; rec., receptor; path., pathway; Transp., transport; subseq., subsequent; mod., modification; inflam., inflammatory; Select., selective; exp., expression; rec., receptors; polar., polarization; initiat., initiation; activ., activation; surf., surface; mol., molecular; apopt., apoptosis.