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Background <p>Diabetes mellitus is associated with low-grade inflammation, resulting in susceptibility to infections and related complications. Histone deacetylase 11 (HDAC11) regulates host immune responses upon infections including fungal and gram-negative bacterial infections. Here, we hypothesise that bacterial infection may influence epigenetic regulation via HDAC11, resulting in the exacerbation of the inflammation responses.</p> Methods <p>Induced pluripotent stem cells (iPSCs) from non-diabetic (ND) and diabetic (DB) donors were differentiated into endothelial cells (ECs). The iPSCs-derived ECs (iPS-ECs) were infected with <i>Escherichia coli (E. coli)</i> to mimic sepsis. Bulk RNA sequencing was performed to validate the gene expression in transcriptomic level. qRT-PCR, ELISA, and western blot were conducted to assess gene expression levels. Immunocytochemistry (ICC) staining was used to visualise the protein expression, and functional tests were performed to assess the iPS-ECs’ response to infection.</p> Results <p>This study revealed that HDAC11 expression is significantly elevated in iPS-ECs derived from DB donors when infected with <i>E. coli</i>. HDAC11 upregulation was associated with increased production of pro-inflammatory cytokines and vascular dysfunction. Administration of a HDAC11 inhibitor effectively suppressed pro-inflammatory cytokine expression and restored endothelial function. Mechanistic analyses demonstrated that interaction of HDAC11 with the signal transducer and activator of transcription 3 (STAT3) sustained the inflammatory response in iPS-ECs derived from DB donors.</p> Conclusion <p>Our findings highlight the role of HDAC11 to mediate inflammation-driven vascular impairment in diabetes, suggesting HDAC11 is a promising therapeutic target to mitigate endothelial dysfunction and inflammation, improving endothelial health in people with diabetes.</p>

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Epigenetic regulation by HDAC11-driven STAT3 activation promotes pro-inflammatory cytokine production and endothelial dysfunction upon bacterial infection in diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Wiwit Ananda Wahyu Setyaningsih,
  • Hojjat Naderi-Meshkin,
  • Andrew Yacoub,
  • Victoria A. Cornelius,
  • Johnatas Dutra Silva,
  • Akbar Satria Fitriawan,
  • Jasenka Guduric-Fuchs,
  • Asim Jamalabdalnaser A. Tashkandi,
  • Refik Kuburas,
  • Anna Zampetaki,
  • Noemi Lois,
  • Alan W. Stitt,
  • Miguel A. Valvano,
  • David J. Grieve,
  • Yaser Atlasi,
  • Anna Krasnodembskaya,
  • Andriana Margariti

摘要

Background

Diabetes mellitus is associated with low-grade inflammation, resulting in susceptibility to infections and related complications. Histone deacetylase 11 (HDAC11) regulates host immune responses upon infections including fungal and gram-negative bacterial infections. Here, we hypothesise that bacterial infection may influence epigenetic regulation via HDAC11, resulting in the exacerbation of the inflammation responses.

Methods

Induced pluripotent stem cells (iPSCs) from non-diabetic (ND) and diabetic (DB) donors were differentiated into endothelial cells (ECs). The iPSCs-derived ECs (iPS-ECs) were infected with Escherichia coli (E. coli) to mimic sepsis. Bulk RNA sequencing was performed to validate the gene expression in transcriptomic level. qRT-PCR, ELISA, and western blot were conducted to assess gene expression levels. Immunocytochemistry (ICC) staining was used to visualise the protein expression, and functional tests were performed to assess the iPS-ECs’ response to infection.

Results

This study revealed that HDAC11 expression is significantly elevated in iPS-ECs derived from DB donors when infected with E. coli. HDAC11 upregulation was associated with increased production of pro-inflammatory cytokines and vascular dysfunction. Administration of a HDAC11 inhibitor effectively suppressed pro-inflammatory cytokine expression and restored endothelial function. Mechanistic analyses demonstrated that interaction of HDAC11 with the signal transducer and activator of transcription 3 (STAT3) sustained the inflammatory response in iPS-ECs derived from DB donors.

Conclusion

Our findings highlight the role of HDAC11 to mediate inflammation-driven vascular impairment in diabetes, suggesting HDAC11 is a promising therapeutic target to mitigate endothelial dysfunction and inflammation, improving endothelial health in people with diabetes.