Researchers from a recent study have identified a key biological pathway responsible for the inflammation seen in psoriasis, with potential implications for other inflammatory diseases like atopic dermatitis, allergic dermatitis, and hidradenitis suppurativa.

The study, published in the journal Immunity, focused on the role of the interleukin-17 (IL-17) pathway and its activation of hypoxia-inducible factor 1-alpha (HIF-1-alpha) in driving psoriasis-related inflammation.

“Our study results broadly show that activation of HIF-1-alpha is at the crux of metabolic dysfunction observed in psoriasis and that its action is triggered by IL-17, another key inflammatory-signaling molecule,” said study author Shruti Naik, PhD, associate professor at NYU Grossman School of Medicine in the Departments of Pathology and Medicine, and the Ronald O. Perelman Department of Dermatology, in a news release.

An analysis of human skin tissue samples from five psoriasis patients revealed similar gene activity patterns for IL-17 and HIF-1-alpha, suggesting a connection. Experimental treatments with the HIF-1-alpha inhibitor BAY-87-2243 in mouse models of psoriasis showed resolution of inflammatory skin lesions. Additionally, treatment with the anti-inflammatory drug etanercept in human patients reduced the activity of both IL-17 and HIF-1-alpha.

Further experiments with psoriasis patient skin samples treated with BAY-87-2243 or standard topical drugs (calcipotriene and betamethasone dipropionate) demonstrated that the HIF-1-alpha inhibitor had a more significant impact on reducing inflammatory gene activity. Genetic analysis of psoriatic skin samples treated with the IL-17A-blocking drug secukinumab confirmed the decrease in HIF-1-alpha activity.

The research also showed that inhibiting glucose uptake in the skin slowed psoriasis progression by reducing glucose metabolism and lactate levels, leading to decreased IL-17 and inflammatory T cells. Disease progression was slowed by targeting lactate production with a topical cream containing lactate dehydrogenase.

“Our findings suggest that blocking either HIF-1-alpha’s action or its glycolytic metabolic support mechanisms could be effective therapies for curbing the inflammation,” Prof. Naik said, who is also the associate director for NYU Langone’s Judith and Stewart Colton Center for Autoimmunity.

“Evidence of HIF-1-alpha’s depressed action, or downregulation, could also serve as a biomarker, or molecular sign, that other anti-inflammatory therapies are working,” added study co-senior investigator Jose U. Scher, MD, the Steere Abramson Associate Professor of Medicine in the Department of Medicine at NYU Grossman School of Medicine.

Source: Subudhi I, et al. Immunity. 2024. Doi10.1016/j.immuni.2024.04.022