Itaconate, a common metabolite, shows promise in MS mouse model

Itaconate, a metabolite produced during cellular energy production activities, was found to restore the balance of immune T cells and reduce multiple sclerosis (MS) symptoms in a mouse model of the disease, a study reported.

The common metabolite specifically suppressed the production of pro-inflammatory T cells while promoting the generation of T-regulatory cells, known as Tregs — an anti-inflammatory cell type associated with autoimmune prevention.

“Our results explain the mechanisms that underlie the modulation of T cell differentiation,” Michihito Kono, MD, PhD, assistant professor at Hokkaido University and study co-lead, said in a university press release.

“This could eventually lead to simple therapeutic approaches which regulate T cell differentiation, thereby treating T cell-mediated autoimmune diseases,” which would include MS, Kono said.

The study, “Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming,” was published in the journal Nature Communications.

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In MS, the immune system mistakenly attacks the myelin sheath, a protective coating around nerve fibers, resulting in inflammation, nerve damage, and the onset of symptoms.

An imbalance in two types of immune cells — Th17 and Tregs — is thought to contribute to the development of MS and other autoimmune conditions, such as lupus. Th17 are a subtype of T helper cells that produce the pro-inflammatory molecule interleukin-17 (IL-17), while Tregs help maintain immune balance and suppress autoimmunity by keeping other immune cells in check.

“Multiple sclerosis (MS) and systemic lupus erythematosus are two of the many autoimmune diseases caused by a dysregulation of T cells,” Kono said. “We were interested in two types of T cells: T helper 17 (Th17) and regulatory T (Treg) cells.”

The balance of T cell subsets largely depends on energy metabolism. Th17 cells produce energy via the glycolysis pathway within the cell’s cytoplasm, outside the nucleus. T-regs, on the other hand, use the power generated by a process called oxidative phosphorylation in mitochondria, which are the powerhouses of cells. These two pathways generate a different set of metabolites which help modulate cellular function.

“These cells have the same origin but have opposite functions in autoimmune diseases, and cell metabolites modulate their action,” Kone said.

Studies suggest that itaconate, a metabolite derived from mitochondrial energy production, can modulate immune responses. But its role in T cell growth and function had not yet been investigated.

“The metabolite we focused on was itaconate (ITA), as it has been shown to have anti-inflammatory, antiviral, and antimicrobial effects,” Kono said.

In initial experiments, Kono and his team incubated itaconate with naive T helper cells, which can differentiate into different T cell types upon activation. The treatment suppressed Th17 growth and promoted Treg differentiation.

Itaconate also blocked the activity of Th17-related genes and significantly reduced the amount of IL-17 produced by Th17 cells.

“These results indicated that ITA regulated Th17 and Treg cell differentiation,” the researchers wrote.

In mice with experimental autoimmune encephalitis, a standard mouse model of MS, treatment with itaconate significantly reduced disease severity and loss of body weight, indicative of poor health, in MS mice compared with untreated controls.

These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.

To exclude the possibility that itaconate had anti-inflammatory effects on other immune cells, mice engineered to lack mature immune B cells and T cells were given Th17 cells pre-treated with itaconate.

Clinical scores and body weight loss also were significantly reduced in mice administered itaconate-treated cells compared with those given cells without treatment. Spinal cord analysis also showed significantly reduced immune cell accumulation and demyelination (loss of myelin) in mice given pre-treated cells.

Further experiments confirmed that other types of immune cells, such as neutrophils, monocytes, and macrophages, were unlikely to account for improvements seen after the administration of itaconate-treated Th17 cells.

Mechanism investigations revealed that itaconate suppressed glycolysis and oxidative phosphorylation, as well as the metabolism of the amino acid methionine, a protein building block, in both cell types.

Itaconate also appeared to modulate the balance of Th17 and T-regs by suppressing the activity of key metabolic enzymes, namely methionine adenosyltransferase and isocitrate dehydrogenase.

“ITA inhibits these pathways by directly inhibiting the enzymes methionine adenosyltransferase and isocitrate dehydrogenase,” Kono said.

The metabolite also altered chromatin, the DNA-protein packages that form chromosomes, by closing in on the gene that encodes IL-17, preventing its production. At the same time, itaconate opened chromatin around Foxp3, stimulating the activity of this gene that regulates the development of T-regs.

“The altered cell metabolites also indirectly affect the chromatin accessibility of essential [gene activity proteins] and the synthesis of proteins required for the differentiation of Th17 and Treg cells,” Kono added.

According to the team, “These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.”