Restoring Immune Balance: Targeting SSAT to Treat Psoriasis and Chronic Inflammation

Original Article: The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation

What are the key takeaways of this article?

A new study published in Immunity highlights a potential breakthrough in psoriasis treatment that involves restoring the function of regulatory T (Treg) cells – a subset of immune cells responsible for controlling excessive inflammatory responses. Unlike conventional treatments that broadly suppress pro-inflammatory pathways and may increase susceptibility to infections, this approach aims to reinstate the Treg cells' natural ability to regulate immune activity.

The research, led by Dr. Georg Stary from the Medical University of Vienna’s Department of Dermatology, focuses on how Treg cells lose their suppressive function in chronic inflammatory skin diseases like psoriasis. Treg cells play a crucial role in maintaining immune balance, particularly in environments dominated by TH17 effector T cells, which drive inflammation. However, under prolonged inflammatory and metabolic stress, Treg cells can become "fragile" and begin producing pro-inflammatory cytokines, despite retaining their defining FoxP3 expression. The study identifies a key enzyme—spermidine/spermine N1-acetyltransferase (SSAT)—as a central player in this dysfunction.

SSAT regulates polyamine metabolism, a process crucial for maintaining the balance between pro- and anti-inflammatory immune responses. When overproduced in Treg cells, SSAT depletes intracellular polyamines, causing Treg cells to adopt a TH17-like pro-inflammatory phenotype. The researchers also discovered that this SSAT-driven transformation is influenced by signaling from inflamed keratinocytes—specifically, the 4-1BB/4-1BBL co-receptor axis—which exacerbates Treg cell dysfunction.

To explore potential therapeutic strategies, the team tested an SSAT inhibitor in a mouse model of psoriasis. Their findings revealed that blocking SSAT could restore the regulatory function of Treg cells, breaking the cycle of excessive immune activation. This suggests that targeted inhibition of SSAT could offer a promising alternative to existing immunosuppressive treatments, which can have significant side effects (i.e., serious infections).

Beyond psoriasis, these findings could have broader implications for other chronic inflammatory diseases, including ulcerative colitis and sarcoidosis, where Treg cell dysfunction and Th-17-driven inflammation play a role. Given the connections between polyamine metabolism, immune aging ("inflammaging"), and inflammatory diseases, modulating SSAT could have potential benefits beyond dermatology.

In summary, while further research is needed to refine this approach and assess its safety in humans, the study provides compelling evidence that restoring Treg cell function through metabolic intervention could lead to more precise and effective treatments for chronic inflammatory conditions.

Publication Date: May 24, 2025

Reference: Neuwirth T, Malzl D, Knapp K, et al. The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation. Immunity. Published online February 25, 2025. doi:10.1016/j.immuni.2025.02.011

Summary By: Miranda Branyiczky