by A recent study published in the journal Immunity reveals that the interleukin-17 (IL-17) pathway, which is targeted by existing anti-inflammatory drugs, instigates the activation of hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriasis. This discovery could pave the way for novel therapies to combat various inflammatory skin diseases, including atopic dermatitis, allergic dermatitis, and hidradenitis suppurativa, according to the researchers.
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The research team, led by investigators at NYU Langone Health, discovered that IL-17, a long-known player in inflammation, activates HIF-1-alpha in psoriasis. Previously, the role of HIF-1-alpha in this context was unclear.
The scientists also found that HIF-1-alpha enables inflamed skin cells to more actively break down sugar for energy, supporting their metabolism and leading to the production of lactate. When consumed by inflammatory T cells, lactate triggers the production of IL-17, fueling even more inflammation.
Examining human skin tissue samples from individuals with psoriasis, the researchers observed similar patterns of gene activity surrounding IL-17 and HIF-1-alpha, suggesting a connection between these factors. In mice engineered to develop psoriasis, treatment with an experimental drug that inhibits HIF-1-alpha, called BAY-87-2243, resolved inflammatory skin lesions.
Additionally, skin samples from 10 patients who had been successfully treated with the anti-inflammatory drug etanercept showed diminished activity for both IL-17 and HIF-1-alpha. This finding implies that when IL-17 is blocked, so is HIF-1-alpha.
Corresponding study author Shruti Naik, Ph.D., associate professor at NYU Grossman School of Medicine in the Departments of Pathology and Medicine, and the Ronald O. Perelman Department of Dermatology, stated, “Our study results demonstrate that HIF-1-alpha activation is at the heart of the metabolic dysfunction observed in psoriasis and that its action is initiated by IL-17, another crucial inflammatory signaling molecule.”
Further experiments were conducted on skin samples from five patients with psoriasis whose healthy and inflamed skin were separately treated with either BAY-87-2243 or an existing combination of topical drugs (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 had a greater effect than existing topical drugs.
Genetic analysis of skin samples from another 24 psoriatic patients treated with the IL-17A–blocking drug secukinumab showed only decreased, not heightened, gene activity connected to HIF-1-alpha when compared to HIF-1-alpha gene activity in nine healthy patients with no psoriatic disease. This indicates that HIF-1-alpha’s blocked action was codependent on blockage of IL-17.
Additional experiments in mice showed that inhibiting glucose uptake in the skin slowed psoriatic disease progression by limiting glycolysis, or glucose metabolism. Both the number of immune T cells tied to inflammation and the cell levels of IL-17 decreased. Researchers also found that levels of lactate, the primary byproduct of glycolysis, in psoriatic skin cell cultures dropped once exposed to the glycolysis-inhibiting drug 2-DG.
Directly targeting lactate production in psoriatic mice using a topical skin cream containing lactate dehydrogenase, which breaks down lactate, also slowed disease progression in the skin, with reduced numbers of inflammatory gamma-delta T cells and reduced IL-17 activity. Gamma-delta T cells were shown to take up lactate and use it to produce IL-17.
Naik concluded, “Our findings suggest that blocking either HIF-1-alpha’s action or its glycolytic metabolic support mechanisms could be effective therapies for curbing inflammation. Additionally, evidence of HIF-1-alpha’s depressed action could serve as a biomarker for other anti-inflammatory therapies.”
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, and director of NYU Langone’s Psoriatic Arthritis Center and the Judith and Stewart Colton Center for Autoimmunity, plans to develop experimental drugs that can block HIF-1-alpha and lactate action in the skin to interrupt the vicious cycle of IL-17–driven inflammation in skin diseases. Scher stated, “Our research significantly expands the scope of feasible therapeutic options.”
Naik emphasizes that while many available therapies for psoriasis, such as steroids and immunosuppressive drugs, reduce inflammation and symptoms, they do not cure the disease. Further experiments are needed to determine which experimental drug is most effective with respect to HIF-1-alpha inhibition before clinical trials can begin. Naik and study co-lead investigators Ipsita Subudhi and Piotr Konieczny have a patent application pending (U.S. application number 63/540,794) for inflammatory skin disease therapies derived from their work on HIF-1-alpha inhibition.
More than 8 million Americans and 125 million people worldwide are estimated to have psoriatic disease. The condition affects men and women equally
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