A modified form of a compound called itaconate suppresses an inflammatory pathway that is overactive in many autoimmune diseases, suggesting that it may be effective against psoriasis as well as multiple sclerosis, rheumatoid arthritis, and lupus, according to a study published in the journal Nature.
Lesional psoriatic skin. Image credit: Wu et al, doi: 10.1371/journal.pone.0005227.
Inflammation is the body’s defense system against infection.
The redness and swelling you see around an infected cut represents the mobilization of a powerful arsenal of cells and molecules in response to injury and invading microbes.
But when inflammation gets misdirected at the body’s own healthy tissues, it causes autoimmune disease, which is why anti-inflammatory drugs are the medication of choice for many autoimmune diseases.
Dr. Maxim Artyomov from the Washington University School of Medicine and co-authors previously had shown that inflammatory cells that detect the presence of bacteria produce itaconate. But surprisingly, rather than amplifying inflammation, itaconate dampens it.
To understand how and why, the team treated inflammatory cells from mice and people with dimethyl itaconate, a modified form of itaconate.
The researchers found that the compound reduces levels of a key protein — known as I?B? (IkappaBzeta) — in the IL-17 inflammatory pathway. This pathway is crucial for fighting off some kinds of bacterial infections, but it is also the body’s primary route to initiating autoimmune disease.
Further, genetic studies of people with psoriasis have found a link between variations in the gene for I?B? and a heightened risk of developing the disfiguring skin disease.
The scientists therefore tested whether reducing protein levels with the itaconate compound could treat psoriasis in mice.
They induced psoriasis-like symptoms in the ears of mice while simultaneously dosing the animals 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 were red and swollen, while the ears of mice that had been treated with dimethyl itaconate looked normal.
Since IL-17 plays a role in so many autoimmune diseases, a compound that puts a check on this pathway potentially could be helpful for treating many serious ailments.
“Since we first linked itaconate to inflammatory cell activation in 2016, it has been surprising us,” Dr. Artyomov said.
“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 multiple sclerosis. This small molecule is turning out to be really powerful.”
Dr. Artyomov and colleagues already have begun studying whether itaconate compounds can reduce the signs of multiple sclerosis in mice.
They are encouraged by structural similarities between dimethyl itaconate and dimethyl fumarate, the active ingredient in an FDA-approved multiple sclerosis drug.
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Monika Bambouskova et al. Electrophilic properties of itaconate and derivatives regulate the I?B?–ATF3 inflammatory axis. Nature 556: 501-504; doi: 10.1038/s41586-018-0052-z
