TY - JOUR
T1 - Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response
AU - Dragomir, Mihnea P.
AU - Fuentes-Mattei, Enrique
AU - Winkle, Melanie
AU - Okubo, Keishi
AU - Bayraktar, Recep
AU - Knutsen, Erik
AU - Qdaisat, Aiham
AU - Chen, Meng
AU - Li, Yongfeng
AU - Shimizu, Masayoshi
AU - Pang, Lan
AU - Liu, Kevin
AU - Liu, Xiuping
AU - Anfossi, Simone
AU - Zhang, Huanyu
AU - Koch, Ines
AU - Tran, Anh M.
AU - Mohapatra, Swati
AU - Ton, Anh
AU - Kaplan, Mecit
AU - Anderson, Matthew W.
AU - Rothfuss, Spencer J.
AU - Silasi, Robert
AU - Keshari, Ravi S.
AU - Ferracin, Manuela
AU - Ivan, Cristina
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Georgescu, Constantin
AU - Banerjee, Pinaki P.
AU - Basar, Rafet
AU - Li, Ziyi
AU - Horst, David
AU - Vasilescu, Catalin
AU - Bertilaccio, Maria Teresa S.
AU - Rezvani, Katayoun
AU - Lupu, Florea
AU - Yeung, Sai Ching
AU - Calin, George A.
N1 - Publisher Copyright:
© 2023, Dragomir et al.
PY - 2023/7/17
Y1 - 2023/7/17
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI158348
DO - 10.1172/JCI158348
M3 - Article
C2 - 37261908
AN - SCOPUS:85165520234
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 14
M1 - e158348
ER -