Cracked, dry hands from psoriasis outbreak. (© IIIRusya – stock.adobe.com)

VIENNA — When your immune system operates correctly, it’s like an elite security team—recognizing threats, mounting defenses, and standing down when the danger passes. Regulatory T cells (Treg cells) function as the security team’s supervisors, ensuring the immune response remains controlled. However, in chronic skin conditions like psoriasis, this regulation becomes impaired.

A new study published in the journal Immunity has identified a metabolic factor contributing to this immune dysfunction. Researchers from the Medical University of Vienna found that an enzyme called SSAT1 plays a crucial role in disrupting Treg cells’ ability to maintain immune balance in skin tissue during inflammation.

“We were able to show that the loss of the anti-inflammatory function of regulatory T cells is caused by a malfunction of the cellular metabolism,” says study leader Georg Stary, from the university’s department of dermatology, in a statement.

This discovery suggests a possible new avenue for treating psoriasis, a condition that affects around 250,000 people in Austria and millions worldwide. Current treatments often require lifelong management and broadly suppress immune function.

How a Single Enzyme Changes Everything

To understand why Treg cells lose control over inflammation in psoriasis and similar diseases, the research team, led by Teresa Neuwirth, Daniel Malzl, and Georg Stary, focused on the enzyme SSAT1. They found that in these conditions, Treg cells produce too much SSAT1, which belongs to the polyamine metabolic pathway—an essential process that influences cell function and survival.

SSAT1 is responsible for breaking down polyamines, molecules that help immune cells function properly. When SSAT1 levels become too high, it depletes these critical molecules, transforming Treg cells from peacekeepers into troublemakers. Instead of calming inflammation, they start producing inflammatory signals, particularly IL-17A, a protein strongly linked to psoriasis and other skin diseases.

This situation is comparable to police officers who, instead of controlling a rowdy crowd, join the rioters. These “fragile” Treg cells maintain their identity markers but completely reverse their function, contributing to inflammation rather than restraining it.

Breaking the Inflammatory Cycle

Interestingly, the study found that SSAT1-driven dysfunction primarily affects Treg cells in the skin rather than other organs. This process appears to be triggered by a specific type of immune response—TH17 inflammation—that plays a major role in psoriasis and similar conditions.

The researchers also discovered that keratinocytes, the main cells in the outer layer of the skin, contribute to this issue. When exposed to inflammation, keratinocytes display a protein called 4-1BBL on their surface. This protein interacts with a receptor on Treg cells called 4-1BB, which increases SSAT1 production and causes Treg cells to switch from suppressing inflammation to promoting it.

With SSAT1 playing such a key role in inflammation, the researchers explored ways to block it. Using lab experiments with human skin cells and a mouse model of psoriasis, they found that inhibiting SSAT1 with a drug called diminazene aceturate (DA) helped restore Treg function. Treated mice had more Treg cells and showed reduced inflammation.

While this result is promising, DA is currently used in veterinary medicine and has side effects that make it unsuitable for long-term human use. However, the study suggests that developing more precise SSAT1 inhibitors could lead to a treatment option with fewer side effects than current therapies.

Beyond Psoriasis: Wider Implications

“Since other chronic inflammatory diseases of the skin or other organs are also characterized by impaired immune regulation, our approach could be important beyond psoriasis,” says Stary, emphasizing the need for further research.

The researchers also found that this metabolic switch wasn’t limited to classic inflammatory conditions like psoriasis. They examined tissue from patients with atopic dermatitis (commonly known as eczema), which is traditionally considered more of an allergic condition. Interestingly, they found evidence of the same SSAT1-driven dysfunction in Treg cells from these patients, suggesting that this mechanism might be a common feature across various types of skin inflammation.

The implications extend beyond skin diseases. Regulatory T-cell dysfunction plays a role in many autoimmune and inflammatory conditions. Understanding how metabolism influences Treg cell function could potentially lead to new therapeutic approaches for conditions ranging from inflammatory bowel disease to rheumatoid arthritis.

The researchers also suggest a connection to aging. As we age, our tissues often experience increased levels of low-grade inflammation—sometimes called “inflammaging”—and our immune regulation becomes less effective. Aging-related diseases are associated with dysregulated polyamines and dysfunctional Treg cell populations, raising the possibility that SSAT1-driven dysfunction might contribute to age-related inflammatory conditions as well.

Although DA itself isn’t suitable for human use, the research lays the groundwork for developing safer drugs that specifically block SSAT1, potentially offering a more effective way to treat chronic inflammatory conditions.