An international research effort led by a team from Swansea University in the U.K. has identified a mitochondrial protein that plays a pivotal role in driving the overactivity of immune cells responsible for autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. The study, published in Nature Communications, has identified the protein ABHD11 as central to the metabolic changes that occur in autoimmunity causing T cells to attack health tissue.
“This research opens up exciting possibilities for developing new treatments that work by adjusting how immune cells use fuels from our diet—a process known as metabolism. ABHD11 could be a valuable target for drugs aimed at reducing inflammation and preventing autoimmune flare-ups, said senior author Nick Jones, PhD, an associate professor at Swansea University Medical School.
The protein ABHD11 is a mitochondrial enzyme that supports the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), an enzyme within the tricarboxylic acid (TCA) cycle. It is involved in several biological processes, including lipid metabolism, 2-oxoglutarate metabolism, and weight gain regulation. When overexpressed or hyperactive in T cells, ABHD11 promotes excessive metabolic activity, driving the production of inflammatory cytokines.
“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),” the researchers wrote. “However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored.”
To study this mechanism, the research team inhibited ABHD11 pharmacologically using two compounds: ML-226, a selective ABHD11 inhibitor used in ex vivo experiments, and WWL222, which was administered daily to mice. Both compounds limited overactivity of T cells and reduced production of inflammatory cytokines. In mouse models of accelerated type 1 diabetes, blocking ABHD11 delayed the onset of the disease, an important finding that could new therapeutic approaches for the disease.
“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 (tricarboxylic acid, or TCA) cycle,” the researchers wrote. This pathway links cellular metabolism to immune regulation, which showed that a metabolic shift triggered by ABHD11 inhibition can dampen inflammation.
The Swansea team’s earlier research and multiple prior studies have pointed to mitochondrial dysfunction as a distinct feature of autoimmune disease, including research showing T cells in rheumatoid arthritis have depleted mitochondrial aspartate and disrupted energy metabolism that promote inflammatory signaling. ABHD11 was also previously identified as one of the genes most strongly associated with remission in rheumatoid arthritis.
The researcher’s work to inhibit ABHD11 resulted in a series of metabolic events that limited T-cell activation. The inhibition increased intracellular lactate and acetyl-CoA, which triggered a sterol regulatory element-binding protein (SREBP2) pathway and boosted oxysterol synthesis, particularly 24,25-EC. This activates LXR signaling, which is known to suppress inflammatory responses in T cells.
Experiments in human cells derived from patients with either rheumatoid arthritis or type 1 diabetes, had the same effects. “Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation,” the researchers wrote.
While the discovery of ABHD11’s role in autoimmunity is an important finding to new research and drug development opportunities, the investigators noted that more work is needed using in vivo models to better understand if it is having a broader effect on the immune system.
Moving ahead, the research team will expand their scope to find any effects to other immune cell types, as well as effects on other autoimmune diseases such as lupus and multiple sclerosis which are also influenced by mitochondrial metabolism. The hope is that finding a way to adjust immune cell metabolism to treat these disorders could mark a significant improvement to current therapies which often have serious side effects.
