A compound called itaconate, derived from immune cells, was shown to ameliorate skin pathology in a mouse model of psoriasis and holds promise for other autoimmune diseases, according to a new study from investigators at Washington University School of Medicine, St. Louis.
The compound suppresses the IL-17-IκBζ inflammatory pathway that is activated in many autoimmune diseases. The study is published April 18 in Nature.
Led by Maxim Artyomov, Ph.D., assistant professor of pathology and immunology, the investigators had previously shown that inflammatory macrophages detect the presence of bacteria that produce itaconate. They discovered that itaconate dampens inflammation. In the current report, they treated inflammatory macrophages from mice and people with dimethyl itaconate, a modified form of itaconate.
They found that dimethyl itaconate reduces levels of IκBζ in the IL-17 pathway, which is the primary pathway in autoimmune disease initiation. They then induced psoriasis-like symptoms in the ears of mice while dosing them with either dimethyl itaconate or placebo every day for a week. By the end of the week, the ears of mice that had received the placebo exhibited signs of psoriasis, while the ears of mice that had been treated with dimethyl itaconate looked normal.
Artyomov and colleagues are studying whether itaconate compounds can reduce the signs of multiple sclerosis (MS) in mice. They are encouraged by structural similarities between dimethyl itaconate and dimethyl fumarate, the active ingredient in a drug approved by the U.S. Food and Drug Administration to treat MS.
“Since we first linked itaconate to inflammatory cell activation in 2016, it has been surprising us,” Artyomov said in a prepared statement. “Everyone thought that if it is produced by inflammatory cells it should fight infection, but no—it’s anti-inflammatory. Now we know that itaconate compounds can help with autoimmune diseases, specifically in psoriasis and potentially in MS. This small molecule is turning out to be really powerful.”
M Bambouskova, L Gorvel, V Lampropoulou, et al. “Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis,” Nature, April 18, 2018. DOI:10.1038/s41586-018-0052-z.