Compound Produced by Immune Cells May Hold Promise for Multiple Sclerosis

A compound produced by immune cells is able to treat psoriasis – a skin disorder – in mice, and may be effective against other autoimmune diseases, such as multiple sclerosis, according to a recent study.

The study, “Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis,” was published in the journal Nature.

Autoimmune diseases occur when the immune system mistakes its own tissues as foreign and induces an inappropriate immune reaction against them. Excessive inflammation – a common feature of these chronic conditions – can cause these misdirected immune responses.

Thus, there is a great interest in therapeutically targeting the inflammatory response, and anti-inflammatory therapies are the treatment of choice for many autoimmune diseases.

Macrophages – a type of white blood cell – are central to the inflammatory response, and they can both induce or decrease inflammation and immune reactions.

Previous work from a team at Washington University School of Medicine in St. Louis, Missouri, showed that activated macrophages produced high levels of a compound called itaconate, which was found to induce anti-inflammatory effects.

Now, the team investigated the mechanisms behind itaconate’s anti-inflammatory effects in human cell lines and in mice.

The addition of dimethyl itaconate – a modified form of itaconate – to human and mice macrophages in the lab reduced the levels of IkappaBzeta, a key protein in the IL-17 inflammatory pathway. This pathway is associated with the development of several autoimmune and inflammatory diseases.

Since mutations of the IkappaBzeta gene have been associated previously with a higher risk of developing psoriasis, researchers examined the effects of dimethyl itaconate in skin cells and in mice with psoriasis-like symptoms in their ears.

Dimethyl itaconate treatment suppressed IkappaBzeta production in human and mouse skin cell lines, and treated psoriasis in mice. These mice had been given dimethyl itaconate every day for a week and by the end of the week showed no signs of psoriasis, when compared with mice that received placebo and showed red and swollen ears.

Multiple sclerosis shares an immune-mediated origin with psoriasis, and dimethyl fumarate has been used to treat both psoriasis – in Europe for more than 20 years – and multiple sclerosis, as the active ingredient of the U.S. Food and Drug Administration-approved therapy Tecfidera.

Having this in mind, along with the fact that dimethyl itaconate has structural similarities to dimethyl fumarate, the team is now studying the effects of itaconate compounds in multiple sclerosis in mice.

“Now we know that itaconate compounds can help with autoimmune diseases, specifically in psoriasis and potentially in multiple sclerosis.” Maxim Artyomov, PhD, said in a press release. Artyomov is an assistant professor of pathology and immunology at Washington University, and the study’s senior author. “This small molecule is turning out to be really powerful,” he said.