According to a new study, a specific biological pathway is responsible for the inflammation observed in the skin disease psoriasis. The findings suggest that this discovery could potentially lead to better treatments for various inflammatory skin conditions, such as atopic and allergic dermatitis, as well as hidradenitis suppurativa. Inflammation is the body’s natural response to irritation and infection, but when it becomes uncontrolled, it can result in the characteristic red, flaky, and itchy lesions associated with these skin diseases.
Conducted by NYU Langone Health researchers, a recent study discovered that the interleukin-17 (IL-17) pathway, which is suppressed by current anti-inflammatory medications, triggers the activation of a protein called hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriasis. While IL-17 has long been recognized as a factor in inflammation, the role of HIF-1-alpha has been unclear up to this point.
The study also revealed that HIF-1-alpha enables inflamed skin cells to more efficiently break down sugar for energy, supporting their metabolism and resulting in the production of a waste product known as lactate. When consumed by inflamed cells, this lactate supports their survival and growth.
The study, published in the journal Immunity online on May 20, revealed that in individuals with psoriasis, there is a connection between the production of IL-17 and HIF-1-alpha. In mice with psoriasis, treatment with a drug that blocks HIF-1-alpha resulted in the resolution of skin inflammation. Additionally, skin samples from 10 patients who were treated with an anti-inflammatory drug showed similar results.etanercept has been found to have reduced activity on both IL-17 and HIF-1-alpha, indicating that blocking IL-17 also blocks HIF-1-alpha. According to Shruti Naik, a corresponding study author and associate professor at NYU Grossman School of Medicine, this study shows that the activation of HIF-1-alpha is central to the metabolic dysfunction seen in psoriasis and is triggered by IL-17, an important inflammatory signaling molecule. Additional tests were conducted on skin samples from five patients with psoriasis.The study looked at patients with psoriasis and compared the effects of a new drug called BAY-87-2243 with a combination of existing topical drugs. The results showed that the BAY-87-2243 had a greater impact on inflammatory gene activity compared to the standard topical drugs. Skin samples treated with BAY-87-2243 showed differences in the expression of 2,698 genes, while samples treated with the standard drugs had differences in the expression of 147 genes. Another 24 psoriasis patients had their skin samples genetically analyzed as part of the study.Patients with psoriatic disease who were treated with the IL-17A-blocking drug secukinumab showed a decrease in gene activity related to HIF-1-alpha, as opposed to an increase when compared to healthy patients with no psoriatic disease. This suggests that the blocked action of HIF-1-alpha was dependent on the blockage of IL-17.
In addition, experiments in mice revealed that blocking glucose uptake in the skin slowed the growth of psoriatic disease by limiting glucose metabolism, or glycolysis. This led to a decrease in the number of immune T cells associated with inflammation and a decrease in the levels of IL-17 in the cells. The researchers also discovered that levels Psoriasis. The study found that levels of lactate, the main result of glycolysis, in cultures of skin cells affected by psoriasis decreased when exposed to the glycolysis-inhibiting drug 2-DG. Additionally, directly targeting lactate production in psoriatic mice with a topical skin cream containing lactate dehydrogenase, which breaks down lactate, slowed the progression of the disease in the skin. This resulted in fewer inflammatory gamma-delta T cells and reduced IL-17 activity. The research also revealed that gamma-delta T cells take up lactate and use it to produce IL-17. These findings suggest that blocking either HIF-1-alpha’s action or its glycolytic metabolic support mechanisms could be effective therapies for Psoriasis.Naik, who is also the associate director for NYU Langone’s Judith and Stewart Colton Center for Autoimmunity, explained that by reducing inflammation, we may be able to slow the progression of autoimmune diseases. The study’s co-senior investigator, Jose U. Scher, MD, added that evidence of HIF-1-alpha’s decreased activity could indicate that other anti-inflammatory treatments are effective. Scher, who also directs NYU Langone’s Psoriatic Arthritis Center and the Judith and Stewart Colton Center for Autoimmunity, emphasized the potential significance of this finding.
plans to create new medications that can hinder the action of HIF-1-alpha and lactate in the skin in order to stop the continuous cycle of IL-17-driven inflammation in skin disease. Our research significantly broadens the range of potential treatment options.”
Naik emphasizes that despite the fact that many existing treatments for psoriasis, such as steroids and immunosuppressive drugs, reduce inflammation and symptoms, they do not provide a cure for the disease. She further stated that additional experiments are necessary to determine which experimental drug is most effective in inhibiting HIF-1-alpha before proceeding with clinical trials. Indeed, Naik and co-lead investigators for the study IPsita Subudhi and Piotr Konieczny are waiting for a patent application (U.S. application number 63/540,794) for therapies for inflammatory skin disease that are based on their work on HIA-1-alpha inhibition.
It is estimated that more than 8 million Americans and 125 million people worldwide have psoriatic disease. This condition affects both men and women equally.
Funding for the studies was provided by National Institutes of Health grants P30AR075043, R01AR080436, R01AI168462, UC2AR081029, K22AI135099, K99AR083536, T32AR069515, TL1TR001447, UL1TR001445, and DP2AR079173. Additionally, there was additional funding provided by the Natio rnrnthe National Psoriasis Foundation, the Judith and Stewart Colton Center for Autoimmunity, the Beatrice Snyder Foundation, the Riley Family Foundation, the American Association of Immunologists, the International Human Frontier Science Program, the Charles H. Revson Foundation, and the Pew-Stewart Scholar Award 00034119, as well as the New York Stem Cell Foundation.
Naik is a member of the advisory boards of Seed Inc. and works as a consultant for BiomX. She also receives funding for her research from Takeda Pharmaceuticals. Scher has provided consulting services for Janssen, Pfizer, UCB, and BMS. He also receives research funding from Janssen and Pfizer. All of these associations are disclosed for transparency.Arrangements are being managed in line with the policies and practices of NYU Langone Health.
Naik, Scher, Subudhi, and Konieczny, along with other NYU Langone investigators, including Aleksandr Prystupa, Rochelle Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine Lu, and Aristotelis Tsirigos, were involved in the study. Other study co-investigators were Niroshana Anandasabapathy from Weill Cornell Medicine; Mayte Suarez-Farinas from the Icahn School of Medicine at Mount Sinai; and Johann Gudjonsson from the University of Michigan.
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