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miR-425-5p improves inflammation and septic liver damage through negatively regulating the RIP1-mediated necroptosis

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Abstract

Objective and design

Sepsis, a systemic inflammatory response syndrome, is still a common cause of death even the patients who are in the intensive care unit. Alleviating septic liver damage may be effective in improving sepsis. Necroptosis and miRNAs have been regarded as a potential target in sepsis.

Material or subjects

The aim of this work is to explain the potential role of miR-425-5p in septic liver damage. LPS was intraperitoneal-injection to C57BL/6 mice for sepsis, and hepatocytes treated with septic serum in vitro. H&E staining for histological evaluation, luciferase reporter assay for target validation, and qRT-PCR, WB, and ELISA analysis for assessment of miR-425-5p, RIP1, inflammatory factors, and LDH levels.

Results

Down-regulated miR-425-5p and up-regulated RIP1/RIP3 were in LPS-induced sepsis mice. Liver damage, RIP1-mediated necroptosis, IL-1β, and TNF-α were suppressed by miR-425-5p agomiR, but further aggravated by miR-425-5p antagomiR. Furthermore, we demonstrated miR-425-5p targeted the 3′UTR of RIP1 mRNA to inhibit RIP1 expression and activated RIP1 reversed miR-425-5p-induced suppression of necroptosis and inflammation in septic hepatocytes.

Conclusions

The data suggest miR-425-5p negatively controls the RIP1-mediated necroptotic signaling cascades and inflammation, and sepsis-related liver damage. miR-425-5p/RIP1 axis is a potential therapeutic strategy for sepsis-related liver damage through necroptosis and inflammation.

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Abbreviations

SIRS:

Systemic inflammatory response syndrome

ICU:

Intensive care unit

RIP1:

Receptor interacting serine/threonine kinase 1

Nec-1:

Necrostatin-1

i.p.:

Intraperitoneal

i.v.:

Intravenous

NC:

Negative control

WB:

Western blot

ELISA:

Enzyme-linked immunosorbent assay

WT:

Wide type

Mut:

Mutation

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Acknowledgements

The work was not funded by any funding opportunity.

Author information

CG and SZ designed the work. CG and CZH performed the experiments, data analysis, and figures. CG wrote the manuscript. SZ reviewed and revised the manuscript. All authors read and approved the manuscript.

Correspondence to Sheng Zhang.

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Gu, C., Hou, C. & Zhang, S. miR-425-5p improves inflammation and septic liver damage through negatively regulating the RIP1-mediated necroptosis. Inflamm. Res. 69, 299–308 (2020). https://doi.org/10.1007/s00011-020-01321-5

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Keywords

  • Septic liver damage
  • miR-425-5p
  • RIP1
  • Necroptosis
  • Inflammation