Energy metabolite has potential to treat MS, autoimmune conditions

The molecule PEP is produced during cellular energy generation

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An oversized hand is seen holding a mouse next to a trio of vials in a lab.

Supplementation with phosphoenolpyruvate (PEP), a molecule produced during cellular energy generation, eased the signs and symptoms of multiple sclerosis (MS) in a mouse model of the disease, a study revealed.

The metabolite inhibited a protein called JunB, which blocked the production of the pro-inflammatory molecule interleukin-17 (IL-17) and suppressed the growth of Th17 cells, an immune cell type that promotes tissue damage in MS and other autoimmune diseases.

Researchers suggested modulating JunB function by PEP or similar molecules may treat these conditions.

“The key to the development of autoimmune diseases, and thus the way to inhibit this development, lies in our cells, but the underlying mechanism has always been unclear,” Hiroki Ishikawa, PhD, study lead author and head of the Immune Signal Unit at the Okinawa Institute of Science and Technology (OIST), Japan said in a news release. “Now, our recent research has shed light on a compound that could suppress the development of these diseases.”

The discovery was detailed in the study, “Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity,” published in Cell Reports.

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Glycolysis and IL-17 production

In many autoimmune conditions, self-reactive Th17 cells — a subtype of immune T helper cells known to produce the signaling protein IL-17 — promote tissue damage. They’ve been shown to participate in the destruction of the myelin sheath, the protective fatty coating around nerve cell fibers that’s progressively lost with MS.

Th17 cell growth and survival rely on glycolysis, a metabolic pathway wherein the sugar molecule glucose is broken down to directly release energy and power cellular processes. By comparison, other T-cells depend largely on the energy produced in mitochondria, separate structures within cells.

While investigating if blocking glycolysis could suppress self-reactive Th17 cells, the researchers discovered that high levels of glycolysis were instead associated with decreased IL-17 production. From this, they wondered whether intermediate metabolites of glycolysis blocked IL-17 production.

“What’s interesting in that excessive glycolysis seems to suppress Th17 cell activity,” said first author Tsung-Yen Huang, a PhD candidate in the Immune Signal Unit. “So, we hypothesized that molecules produced during glycolysis may inhibit the cells.”

To find out, the researchers grew Th17 cells in the presence of different glycolysis metabolites. One metabolite, called PEP, significantly suppressed IL-17 production without affecting overall cell health.

Supplementation with high doses of PEP increased this metabolite’s levels in Th17 cells and suppressed IL-17 production independent of its role in glycolysis, they showed.

The researchers then set out to determine the molecular mechanisms involved in PEP-associated inhibition of Th17 cells. Experiments revealed the metabolite blocked the activity of genes regulated by a protein complex composed of JunB, BATF, and IRF4.

However, PEP didn’t appear to affect the production of these proteins. Instead, it interacted with JunB, blocking the complex from binding to DNA and activating the gene that encodes IL-17.

To extend these findings to a living animal, mice were treated with daily under-the-skin injections of PEP. Consistent with its effects in lab dishes, the treatment markedly decreased IL-17 production in the animals’ lymph nodes and spleens, and suppressed the generation of Th17 cells.

Finally, treating mice with experimental autoimmune encephalomyelitis, a commonly used model of MS, with high-dose PEP (1g/kg) significantly reduced MS-like symptoms, “suggesting therapeutic potential of PEP for Th17-mediated autoimmune disorders,” the researchers noted. “An approach utilizing PEP or its derivatives to modulate JunB function may have potential for selective therapy of autoimmunity.”

“Our results show the clinical potential of PEP. But first we need to increase its efficiency,” Huang said, referring to the need for high doses of PEP to ease disease severity in the mouse model.