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<p>α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.</p>

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Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月3日

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  • Benjamin J. Jenkins,
  • Yasmin R. Jenkins,
  • Fernando M. Ponce-Garcia,
  • Chloe Moscrop,
  • Iain A. Perry,
  • Matthew D. Hitchings,
  • Alejandro H. Uribe,
  • Federico Bernuzzi,
  • Simon Eastham,
  • James G. Cronin,
  • Ardena Berisha,
  • Alexandra Howell,
  • Joanne Davies,
  • Julianna Blagih,
  • Marta Williams,
  • Morgan Marsden,
  • Douglas J. Veale,
  • Luke C. Davies,
  • Micah Niphakis,
  • David K. Finlay,
  • Linda V. Sinclair,
  • Benjamin F. Cravatt,
  • Andrew E. Hogan,
  • James A. Nathan,
  • Ian R. Humphreys,
  • Ursula Fearon,
  • David Sumpton,
  • Johan Vande Voorde,
  • Goncalo Dias do Vale,
  • Jeffrey G. McDonald,
  • Gareth W. Jones,
  • James A. Pearson,
  • Emma E. Vincent,
  • Nicholas Jones

摘要

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.