Key growth factor protects gut from inflammatory bowel disease
Date:
January 31, 2022
Source:
Weill Cornell Medicine
Summary:
A growth factor protein produced by rare immune cells in the
intestine can protect against the effects of inflammatory bowel
disease (IBD), according to a new discovery.
FULL STORY ==========================================================================
A growth factor protein produced by rare immune cells in the intestine
can protect against the effects of inflammatory bowel disease (IBD),
according to a new discovery from Weill Cornell Medicine researchers.
==========================================================================
In their study, published Jan. 31 in Nature Immunology, the researchers
found that the growth factor, HB-EGF, is produced in response to gut inflammation by a set of immune-regulating cells called ILC3s. These
immune cells reside in many organs including the intestines, though
their numbers are known to be depleted in the inflamed intestines of
IBD patients.
The researchers showed in experiments in mice that this growth factor
can powerfully counter the harmful effects of a key driver of intestinal inflammation called TNF. In doing so, ILC3s protect gut-lining cells when
they would otherwise die and cause a breach in the intestinal barrier.
"We've discovered a new cellular pathway that is essential to protect
against gut inflammation. This discovery could lead to a better
understanding of IBD pathogenesis and new strategies to treat this
disease" said study senior author Dr. Gregory Sonnenberg, an associate professor of microbiology and immunology in medicine in the Division
of Gastroenterology & Hepatology and a scientist in the Jill Roberts
Institute for Research in Inflammatory Bowel Disease at Weill Cornell
Medicine.
IBD, a disease category including ulcerative colitis and Crohn's disease, features chronic gut inflammation and many potential follow-on effects including arthritis and colorectal cancer. The condition appears to be
quite common in the United States; a survey-based study by researchers at
the Centers for Disease Control and Prevention in 2015 suggested that more
than 1 percent of the U.S. population -- more than three million people --
were living with IBD. Current treatments help some but not all patients.
Dr. Sonnenberg and his laboratory have found in recent studies that ILC3s
play a key role in protecting the gut from harmful inflammation and are depleted in human patients who have IBD or colon cancer. In the new study,
the team sought a more precise understanding of how ILC3s fight against
IBD's inflammatory effects.
==========================================================================
The researchers in an initial set of experiments recreated an IBD-like condition in mice using high doses of an inflammatory immune protein
called TNF, a major driver of inflammation in IBD and the target of
some IBD therapies. They found in these experiments that ILC3s strongly
protect the gut linings of the mice from TNF-induced inflammatory damage
-- mice lacking ILC3s suffered significantly worse damage.
Prior studies have suggested that ILC3s help protect the gut at least
in part by producing an immune protein called IL-22, which promotes
gut barrier function. However, the mouse experiments in the new
study indicated that ILC3s' gut-protecting effect against TNF works independently of IL-22.
Using a relatively advanced technique called single-cell RNA sequencing,
the researchers eventually zeroed in on the mechanism of ILC3s' protective effect: the growth factor protein HB-EGF, which they showed could
specifically keep gut-lining cells alive in the presence of excessive TNF.
The team found that ILC3s are the dominant producers of HB-EGF in the
gut. They were able to identify the cascade of signaling factors that
occurs downstream of TNF and causes ILC3 to switch on HB-EGF production --
and they observed the same cascade in human ILC3s, indicating that these findings are not just specific to mice. The researchers also confirmed
from analyses of IBD-patient gut tissue that HB-EGF-producing ILC3s are
reduced in areas of gut inflammation.
The findings reveal a key mechanism that the gut normally uses to protect itself from harmful inflammation and suggest that the loss of ILC3s is
at least one reason this mechanism fails in IBD.
"Identifying the significance of this pathway is a good first step,
and we're now thinking about how we might manipulate this pathway to
benefit IBD patients," Dr. Sonnenberg said.
The loss of ILC3s in the IBD gut poses a challenge to the development of therapeutic solutions that depend on ILC3s, he noted. Moreover, though
the growth factor HB-EGF on its own could be therapeutic, even if ILC3s
are depleted, HB-EGF has been linked to the faster growth of a variety
of cancers.
"Our ongoing research is interrogating the role of this ILC3 and HB-EGF
pathway in the development of chronic-inflammation-related colon cancer,"
said study first author Dr. Lei Zhou, a postdoctoral associate in the Sonnenberg laboratory. "It will be important to delineate the exact
cellular and molecular mechanisms by which this novel pathway coordinates intestinal health, inflammation and cancer before moving forward with manipulating it as a therapeutic strategy." The Sonnenberg Laboratory is supported by the National Institutes of Health (R01AI143842, R01AI123368, R01AI145989, R01AI162936, R21CA249284 and U01AI095608), the NIAID Mucosal Immunology Studies Team (MIST), the Crohn's and Colitis Foundation, the
Searle Scholars Program, the American Asthma Foundation Scholar Award,
Pilot Project Funding from the Center for Advanced Digestive Care (CADC),
an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute
(CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative
Research Initiative, the Dalton Family Foundation, Linda and Glenn
Greenberg, and the Roberts Institute for Research in IBD. Gregory
F. Sonnenberg is a CRI Lloyd J. Old STAR. Lei Zhou is supported by a
fellowship from the Crohn's and Colitis Foundation (608975).
========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Lei Zhou, Wenqing Zhou, Ann M. Joseph, Coco Chu, Gregory G. Putzel,
Beibei Fang, Fei Teng, Mengze Lyu, Hiroshi Yano, Katrin
I. Andreasson, Eisuke Mekada, Gerard Eberl, Gregory
F. Sonnenberg. Group 3 innate lymphoid cells produce the growth
factor HB-EGF to protect the intestine from TNF-mediated
inflammation. Nature Immunology, 2022; DOI: 10.1038/
s41590-021-01110-0 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/01/220131132806.htm
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