A serendipitous finding lends new insight into how atopic dermatitis
develops

Date:
February 14, 2022
Source:
University of Pennsylvania
Summary:
New research reveals a mechanism behind the inflammation that is
a feature of the common skin disease.



FULL STORY ========================================================================== Atopic dermatitis, a common skin condition affecting both children
and adults, is often thought of as an inflammatory disease that
arises from a breakdown in the barrier function of the skin. Now a
new study pinpoints a cascade of inflammatory signaling that precedes
the appearance of skin ulcers, shedding light on the early stages of
the condition and identifying potential novel molecular targets for
therapeutic intervention.


==========================================================================
The work, published in the journal Science Translational Medicine,
was the result of a cross-school and cross-institutional collaboration
among researchers at the University of Pennsylvania's School of Dental
Medicine and Perelman School of Medicine, Oak Ridge National Laboratory,
and the University of Tennessee.

"You have researchers in the dental school noticing a skin condition, broadening their work to the medical school and experts on computational systems biology," says Dana Graves, a co-corresponding author on the
paper and a professor and vice dean for research and scholarship at Penn
Dental Medicine.

"Without this interdisciplinary collaboration, that initial finding would
not have gone anywhere." John Seykora, a co-corresponding author and
professor of dermatology at Penn Medicine, seconds that observation. "This shows one of the benefits of being part of a university with experts
across fields," he says. "Our dental school colleagues developed a mouse
that manifested a particular skin phenotype, and the question was, What
was this and did it resemble any disease we might know? And in the end
it did, and it's providing some novel insights into a very common skin condition in humans." The work began in Graves' lab, with Kang Ko, then
a student in the Doctor of Science in Dentistry program and now a Penn
Dental Medicine assistant professor, leading an exploration of the role
of inflammatory signaling in bone fracture healing in diabetes. A focus
was on nuclear factor kappa-B (NF-kB), a master regulator of inflammatory responses. As part of that work, Ko, Graves, and colleagues developed
a mouse model lacking an activator of NF-kB signaling, IKKB.

The researchers noticed that these animals developed skin lesions as
they became young adults.



========================================================================== "That was interesting to us because these ulcerations looked like an inflammatory event, but we had effectively turned off the activity of
NF-kB, which should reduce inflammation," says Graves. "So this was
a paradox." To better understand what was driving this response, they
sought expertise in skin diseases.

"As someone who studies bone and oral biology, the topic of dermatology
was obviously a little different," says Ko.

Ko and Graves knew of Seykora from a talk he had given about the Cutaneous Phenomics and Transcriptomic core which he directs, part of Penn's Skin
Biology and Diseases Research-based Center housed in Dermatology. When
Seykora and colleagues examined the mice, they noted several features
quite similar to atopic dermatitis, "albeit the mouse version," he says.

In particular, they noted skin thickening and an infiltration of
certain types of white blood cells that are also seen in human atopic dermatitis. Drilling deeper into how the loss of IKKB was driving these effects, the team performed single-celled RNA analysis, a technique
that gives a read out of which RNA transcripts are present in individual
cells. They then teamed with computational systems biology experts Daniel Jacobson of Oak Ridge National Laboratory and his student Jean Merlet at
the University of Tennessee who, along with other students in Jacobson's
lab, had developed a new explainable-AI based method for analyzing
single-cell RNA sequencing data. Together, the team discovered that the
cell type that appeared responsible for these effects was fibroblasts,
a major component of the skin's dermis layer and typically thought to
support the structural integrity of skin.



==========================================================================
"We are excited that these new methods that we have developed for
single-cell RNA-seq analysis have led the discovery of such exciting
biology implicating the important role that NF-kB plays in fibroblasts
in the context of atopic dermatitis" says Jacobson. "We believe that
this type of transdisciplinary collaboration is crucial for solving
the challenging problems that we face in complex biological systems."
Though NF-kB typically promotes inflammation, here, decreased NF-kB
activity was paradoxically leading to recruitment of immune cells and associated inflammation. Data from the team's single-cell RNA analysis
pointed to a protein transcription factor called CEBPB as being strongly activated in the fibroblasts lacking IKKB. CCL11 was likewise highly
active in these fibroblasts. Also known as eotaxin, CCL11 is a signaling molecule that promotes inflammation by recruiting a class of white blood
cells called eosinophils, to its location. "We worked out the mechanism
in the mouse," Sekora says, "then showed that much of it applied in
human tissue as well." When the researchers compared what they had seen
in the mouse cells to skin samples from people with atopic dermatitis,
they found similar patterns; CCL11 and CEBPB were both found at higher
levels in the affected skin than in unaffected skin. They also conducted parallel experiments in human skin fibroblasts, using an inhibitor to
IKKB, and observed that levels of CCL11 rose dramatically.

Moving back to the mouse model, the researchers found that introducing a monoclonal antibody against CCL11 tamped down the inflammatory response
they had initially seen in animals lacking IKKB, suggesting that this
pathway could be one to target to reduce atopic dermatitis-associated inflammation.

Not only does the work point to a new approach to therapeutic development
for atopic dermatitis, but the researchers say it underscores a developing appreciation that fibroblasts play important roles in immune processes
in the skin.

"An important finding from our study was fibroblasts can modulate
immune cells," says Ko. "Our results, along with recent reports in other inflammatory conditions, indicate the fibroblasts are important regulators
of white blood cells." Atopic dermatitis is a disease that typically
emerges in childhood, often manifesting along with asthma. Indeed, in
the mice, too, the signaling abnormalities the researchers observed
occurred in a period corresponding to the animals "childhood." The
group's findings suggest that fibroblasts may be involved during this
period in helping to establish appropriate immune signaling in the skin.

"We have viewed NF-kB as a factor that stimulates inflammation, but it
could be that, during development, its activation might be important
for maintaining homeostasis," says Graves.

In follow-up research, Graves, Ko, Seykora, and Jacobson are continuing
their collaboration, trying to further explore NF-kB signaling in
fibroblasts.

"Our goal is to further refine these studies and extend them," says
Seykora.

"If all of this bears out, then perhaps we can get people interested
in targeting some of these pathways with new treatments." Ko, Graves,
Seykora, and Jacobson's coauthors were Penn Dental Medicine's Brett
P. DerGarabedian, Huang Zhen, Eileen Hu, Anh T. Nguyen, and Faizan Alawi;
Penn Medicine's Yoko Suzuki-Horiuchi, Matthew L. Hedberg, Stephen Prouty, Matthew C.

Walsh, and Yongwon Choi; Sarah E. Millar of the Icahn School of Medicine
at Mount Sinai; Jean J. Merlet, Ashley Cliff, and Jonathon Romero of
the University of Tennessee; and Michael R. Garvin of Oak Ridge National Laboratory.

Seykora, Jacobson, and Graves were co-corresponding authors on the
work. Ko and Merlet were co-lead authors.

The study was supported by the National Institutes of Health (grants
DE019108, DE027129, AR069589, DE030415, DA051908, AR007465, and ES028114).

========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kang I. Ko, Jean J. Merlet, Brett P. DerGarabedian, Huang Zhen, Yoko
Suzuki-Horiuchi, Matthew L. Hedberg, Eileen Hu, Anh T. Nguyen,
Stephen Prouty, Faizan Alawi, Matthew C. Walsh, Yongwon Choi,
Sarah E. Millar, Ashley Cliff, Jonathon Romero, Michael R. Garvin,
John T. Seykora, Daniel Jacobson, Dana T. Graves. NF-kB perturbation
reveals unique immunomodulatory functions in Prx1 fibroblasts that
promote development of atopic dermatitis. Science Translational
Medicine, 2022; 14 (630) DOI: 10.1126/scitranslmed.abj0324 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214095643.htm

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