Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
Abstract
Abstract 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.
Article Details
Authors (34)
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
Department of Molecular Genetics, University of Texas Southwestern Medical Center
Gareth W. Jones
James A. Pearson
Emma E. Vincent
Nicholas Jones