NEW
YORK, May 20, 2024 /PRNewswire/ -- A certain
biological pathway, a set of linked reactions in the body, drives
the inflammation seen in the skin disease psoriasis, a new study
finds. The work could lead to improved therapies for all
inflammatory skin diseases, including atopic and allergic
dermatitis and a type of boil called hidradenitis suppurativa, say
the study authors. Inflammation is the body's natural response to
irritation and infection, but when out of control, it can lead to
the reddish, flaky, itchy lesions that come with these skin
diseases.
Led by researchers at NYU Langone Health, the new study found
that the interleukin-17 (IL-17) pathway, whose activity is blocked
by existing anti-inflammatory drugs, activates a protein called
hypoxia inducible factor 1-alpha (HIF-1-alpha) in psoriasis.
Researchers say that IL-17 has long been known to be active in
inflammation, but the role of HIF-1-alpha has until now been
unclear.
The research team also found that HIF-1-alpha let inflamed skin
cells more actively break down sugar for energy, supporting their
metabolism and leading to the production of a waste product called
lactate. When consumed by inflammatory T cells, lactate triggered
production of IL-17, fueling even more inflammation.
Publishing in the journal Immunity online
May 20, the findings show that in
human skin tissue samples from people with psoriasis, measures of
gene activity around IL-17 and HIF-1-alpha were similar, suggesting
that these factors are interconnected. Experiments in mice treated
to develop psoriasis found that subsequent treatment with an
experimental drug that blocks the action of HIF-1-alpha, called
BAY-87-2243, resolved inflammatory skin lesions.
Further, skin samples from 10 patients successfully treated with
anti-inflammatory drug etanercept showed diminished activity for
both IL-17 and HIF-1-alpha, suggesting to researchers that when
IL-17 is blocked, so is HIF-1-alpha.
"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 corresponding 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.
Further experiments were performed on skin samples from five
patients with psoriasis whose healthy and inflamed skin was
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. Specifically, skin samples that responded to
HIF-1-alpha therapy had 2,698 genes that were expressed
differently, while standard-of-care–treated samples had 147
differently expressed genes.
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. Researchers say this
indicates HIF-1-alpha's blocked action was codependent on blockage
of IL-17.
Additional experiments in mice showed that blocking sugar
(glucose) uptake in the skin slowed psoriatic disease growth by
limiting glucose metabolism, or glycolysis. Both the number of
immune T cells tied to inflammation and the cell levels of IL-17
also decreased. The researchers found further that levels of
lactate, the main 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.
"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," added Naik, 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," said 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.
Scher, who also serves as director of NYU Langone's Psoriatic
Arthritis Center and the Judith and Stewart Colton Center for
Autoimmunity, says the team plans to develop experimental drugs
that can block HIF-1-alpha and lactate action in the skin "to end
the underlying vicious cycle of IL-17–driven inflammation in skin
disease. Our research fundamentally expands the scope of feasible
therapeutic options."
Naik points out that while many available therapies for
psoriasis, including steroids and immunosuppressive drugs, reduce
inflammation and symptoms, they do not cure the disease.
She said further experiments are needed to refine which
experimental drug works best, with respect to HIA-1-alpha
inhibition, before clinical trials could start. Indeed, 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 HIA-1-alpha inhibition.
More than 8 million Americans and 125 million worldwide are
estimated to have psoriatic disease. The condition affects men and
women equally.
Funding support for the studies was provided by National
Institutes of Health grants P30AR075043, R01AR080436, R01AI168462,
UC2AR081029, K22AI135099, K99AR083536, T32AR069515, TL1TR001447,
UL1TR001445, and DP2AR079173. Additional funding was provided by
the 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 serves on the advisory boards of Seed Inc. and as a
consultant for BiomX. She also receives research funding from
Takeda Pharmaceuticals. Scher has served as a consultant for
Janssen, Pfizer, UCB, and BMS. He also receives research funding
from Janssen and Pfizer. All of these arrangements are being
managed in accordance with the policies and practices of NYU
Langone Health.
Besides Naik, Scher, Subudhi, and Konieczny, other NYU Langone
investigators were Aleksandr
Prystupa, Rochelle Castillo,
Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana
Reznikov, Ikjot Sidhu, Cynthia
Loomis, Catherine Lu, and
Aristotelis Tsirigos. Other study
co-investigators were Niroshana Anandasabapathy, at Weill Cornell
Medicine; Mayte Suarez-Farinas, at
the Icahn School of Medicine at Mount
Sinai; and Johann Gudjonsson,
at the University of Michigan.
Contact: Gregory Williams,
gregory.williams@nyulangone.org
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SOURCE NYU Langone Health