A study by researchers at NYU Langone Health has identified a critical biological pathway driving inflammation in psoriasis, potentially paving the way for the development of improved therapies for a range of inflammatory skin diseases. The findings, published in the journal Immunity, help clinicians understand the complex interplay between immune response and cellular metabolism in chronic skin conditions.
The research team, led by Shruti Naik, PhD, identified that the interleukin-17 (IL-17) pathway activates the protein hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriatic skin. This activation triggers a cascade of metabolic changes, including increased glucose breakdown and lactate production, which further fuels 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-signalling molecule,” Dr. Naik said in a press release. She is associate professor at NYU Grossman School of Medicine in the Departments of Pathology and Medicine, and the Ronald O. Perelman Department of Dermatology.
The researchers found that skin samples from 10 patients successfully treated with etanercept showed diminished activity for both IL-17 and HIF-1-alpha, suggesting that when IL-17 is blocked, HIF-1-alpha is as well.
To investigate these results, the team developed an experimental topical skin cream containing lactate dehydrogenase called BAY-87-2243 that blocks HIF-1-alpha action. In mice with induced psoriasis, the cream effectively resolved inflammatory skin lesions.
The next step assessed skin samples from five patients with psoriasis whose healthy and inflamed skin was separately treated with BAY-87-2243 or an existing combination of topical therapies (calcipotriene and betamethasone dipropionate). Researchers then compared differences in inflammatory gene activity as a measure of impact and found that the HIF-1-alpha inhibitor BAY-87-2243 had a greater effect than existing topical drugs and demonstrated that blocking HIF-1-alpha action could effectively resolve inflammatory skin lesions.
“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,” said Dr. Naik, who is also the associate director for NYU Langone's Judith and Stewart Colton Center for Autoimmunity.
Further investigations revealed that targeting lactate production directly could also slow disease progression. The topical skin cream BAY-87-2243 containing lactate dehydrogenase, which breaks down lactate, reduced the number of inflammatory gamma-delta T cells and IL-17 activity in psoriatic mice.
Dr. Jose U. Scher, co-senior investigator of the study, emphasized the potential of these findings: “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.”
The researchers believe their work could lead to more targeted therapies that address the underlying metabolic dysfunction in other inflammatory skin diseases such as atopic and allergic dermatitis and hidradenitis suppurativa.
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