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The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated

Zhuo Zeng1, Yingying Lan1, Lijuan Zhang1

  • 1Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.

Burns & Trauma
|November 29, 2023
PubMed
Abstract

Insights

YTHDF2 acts as an inflammation inhibitor in sepsis by reducing HMGB1 release. This mechanism involves suppressing the IL-6R/JAK2/STAT1 pathway, highlighting YTHDF2 as a potential therapeutic target for sepsis.

Area of Science:

  • Molecular Biology
  • Immunology
  • Biochemistry

Background:

  • Sepsis is a severe complication in burn victims, characterized by a dysregulated inflammatory response.
  • YTH domain family 2 (YTHDF2), an m6A reader, is involved in eukaryotic cellular processes, but its role in sepsis remains unexplored.

Purpose of the Study:

  • To investigate the effects and underlying mechanisms of YTHDF2 in sepsis.
  • To determine if YTHDF2 can serve as a therapeutic target for sepsis.

Main Methods:

  • Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot to assess protein and mRNA expression.
  • Enzyme-linked immunosorbent assays (ELISAs) to measure inflammatory cytokine levels.
  • RNA immunoprecipitation and dual-luciferase reporter assays to confirm YTHDF2 targeting of IL-6R mRNA.
  • A mouse model of lipopolysaccharide (LPS)-induced sepsis to validate findings in vivo.

Main Results:

  • YTHDF2 expression was found to be low in septic conditions (mice, patients, and LPS-induced cells).
  • Overexpression of YTHDF2 reduced inflammation by inhibiting HMGB1 release and the JAK2/STAT1 signaling pathway in LPS-stimulated cells.
  • YTHDF2 suppresses IL-6R mRNA stability, thereby inhibiting HMGB1 release and the IL-6R/JAK2/STAT1 axis, demonstrating a protective role in septic mice.

Conclusions:

  • YTHDF2 acts as a crucial inhibitor of inflammation in sepsis.
  • YTHDF2 reduces HMGB1 release by modulating the IL-6R/JAK2/STAT1 pathway.
  • YTHDF2 represents a novel therapeutic target for sepsis interventions.
Keywords:
InflammationJanus kinase 2SepsisYTH domain family 2high-mobility group box-1interleukin 6 receptorsignal transducer and activator of transcription 1

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