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Purpose <p>Sepsis, a potentially fatal condition resulting from a dysregulated immune response to infection, is often associated with immunosuppression. Interferon regulatory factor 4 (IRF4), a key regulator of T-cell function, plays an important role in this process. This study aimed to investigate the effects of IRF4 on splenic CD4<sup>+</sup> T lymphocytes in the spleens of septic mice during the immunosuppressed phase and to elucidate the mechanisms regulating its expression.</p> Methods <p>An immunosuppressed state was induced in mice using the cecal ligation and puncture model. The MEK inhibitor trametinib was administered to suppress IRF4 expression, enabling evaluation of its role in immunosuppression. MeRIP–qPCR, RIP–qPCR, and dual-luciferase reporter assays were performed to investigate the regulatory mechanisms underlying IRF4 upregulation.</p> Results <p>IRF4 was upregulated in immunosuppressed septic mice.&#xa0;Treatment with trametinib suppressed IRF4 expression, thereby alleviating the immunosuppressed state. Methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification enhanced the binding of&#xa0;YTH N6-methyladenosine RNA-binding protein 1 to IRF4 mRNA, promoting its translation. METTL3 depletion reduced IRF4 expression, alleviated immunosuppression, and improved survival.</p> Conclusion <p>Our findings highlight the critical regulatory role of IRF4 in sepsis-induced immunosuppression. The identification of m6A modification as a mechanism regulating IRF4 expression reveals a novel potential avenue for therapeutic intervention.</p>

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High expression of IRF4 mediated by m6A modification promotes immunosuppression in the late phase of sepsis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Ziying Xiong,
  • Wending Zhou,
  • Nengyi Hua,
  • Xuedi Zhang,
  • Chunxiu Ling,
  • Xiao Huang,
  • Xiaolei Liu,
  • Hanhui Zhong,
  • Shuhua Luo,
  • Huiling Zhang,
  • Bowan Huang,
  • Jing Tang

摘要

Purpose

Sepsis, a potentially fatal condition resulting from a dysregulated immune response to infection, is often associated with immunosuppression. Interferon regulatory factor 4 (IRF4), a key regulator of T-cell function, plays an important role in this process. This study aimed to investigate the effects of IRF4 on splenic CD4+ T lymphocytes in the spleens of septic mice during the immunosuppressed phase and to elucidate the mechanisms regulating its expression.

Methods

An immunosuppressed state was induced in mice using the cecal ligation and puncture model. The MEK inhibitor trametinib was administered to suppress IRF4 expression, enabling evaluation of its role in immunosuppression. MeRIP–qPCR, RIP–qPCR, and dual-luciferase reporter assays were performed to investigate the regulatory mechanisms underlying IRF4 upregulation.

Results

IRF4 was upregulated in immunosuppressed septic mice. Treatment with trametinib suppressed IRF4 expression, thereby alleviating the immunosuppressed state. Methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification enhanced the binding of YTH N6-methyladenosine RNA-binding protein 1 to IRF4 mRNA, promoting its translation. METTL3 depletion reduced IRF4 expression, alleviated immunosuppression, and improved survival.

Conclusion

Our findings highlight the critical regulatory role of IRF4 in sepsis-induced immunosuppression. The identification of m6A modification as a mechanism regulating IRF4 expression reveals a novel potential avenue for therapeutic intervention.