The yin and yang of inflammation controlled by a single molecule

Date:
August 5, 2020
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers have now identified a protein called histone deacetylase
3 (HDAC3) as the orchestrator of the immune system's inflammation
response to infection. By using both specially cultured cells and
small animal models, HDAC3 was found to be directly involved in
the production of agents that help kill off harmful pathogens
as well as the restoration of homeostasis, the body's state
of equilibrium. This work shows that some of the methods being
tested to fight cancer and harmful inflammation, such as sepsis,
that target molecules like HDAC3 could actually have unintended
and deadly consequences.



FULL STORY ========================================================================== Researchers from the Perelman School of Medicine at the University of Pennsylvania have now identified a protein called histone deacetylase 3
(HDAC3) as the orchestrator of the immune system's inflammation response
to infection.

By using both specially cultured cells and small animal models, HDAC3
was found to be directly involved in the production of agents that help
kill off harmful pathogens as well as the restoration of homeostasis,
the body's state of equilibrium. This work, published in Nature, shows
that some of the methods being tested to fight cancer and harmful
inflammation, such as sepsis, that target molecules like HDAC3 could
actually have unintended and deadly consequences.


==========================================================================
"Our work shows that HDAC3 is key to the innate immune response due
to the yin and yang of its responsibilities -- both triggering and
reducing inflammation," said senior author Mitchell A. Lazar, MD,
PhD, director of the Institute for Diabetes, Obesity, and Metabolism
(IDOM). "Now that we understand this, it is now much clearer what needs
to be targeted when medications are tested and used to counter potentially deadly inflammation." Inflammation is a highly complex defense mechanism employed by the innate immune system, meaning that it's something someone
is born with and not acquired later like other parts of the immune
system. Although inflammation is famous for the appearance of swelling,
it also includes changes in blood flow and blood vessel permeability
and the migration of white blood cells. When well-orchestrated, the inflammatory response should quickly and precisely locate and eliminate
danger before subsiding to anti-inflammatory processes that help with the removal of damaged tissues so that the body can begin to heal and repair.

However, the body's inflammation response could also damage it. Hence,
when this rise-and-fall in inflammatory factors go unchecked,
diseases like cancer, heart disease, diabetes and even COVID-19 can be developed. Too much inflammation can cause things like septic shock, which causes multiple organ failures within the body due to an uncontrolled
"cytokine storm," a phenomenon also widely reported in patients infected
with COVID-19.

Thus, the discovery of HDAC3 as an inflammatory orchestrator has
widespread implications. In the study, the researchers used multiple
advanced genomic technologies to isolate and locate HDAC3. This protein functions largely as an enzyme, which is a catalyst that brings on
different reactions in the body. The team was able to discover the
mechanism by which it switches between its different enzymatic states,
an ability that allows it to both activate and repress inflammation
response, a yin and yang type of existence.

To test what the enzyme did practically, the researchers looked at
how mouse models responded to a toxin in three different ways. First,
they looked at models lacking HDAC3 in their macrophages, the cells
that the immune system uses to destroy harmful presences within the
body. There, high levels of protection against the infectious toxin were observed. In different models, when HDAC3 was present and allowed to
operate its typical enzyme functions, there was moderate protection and
a mortality that aligned with what was expected when this type of toxin
was present. But in the third model, when HDAC3's enzyme activities were totally blocked by replacing it with a mutant form of itself, lethality
went through the roof and sepsis set in.



==========================================================================
"We showed that it's the non-enzymatic functions of HDAC3, previously
under- appreciated, that are responsible for the production of the
cytokine storm and increased lethality," said the study's lead author,
Hoang C. B. Nguyen, an MD/ PhD student in the Lazar Lab at the Perelman
School of Medicine. "The enzymatic functions of HDAC3 on the other hand, actually help 'quench' the non-enzymatic functions. When the non-enzymatic functions exist in isolation, it's unchecked and harmful." It's important
to note that this all only applies to HDAC3 in macrophages.

While a lack of HDAC3 molecules in those immune system cells produced
the best result, efforts to totally remove it from the human body could
be disastrous, as it helps form cells the body needs to live.

Moving forward, the researchers hope that their work will inform work
being done on the pharmaceutical level. There has been a focus on HDAC inhibitors as a method to fight cancer and inflammation.

"It has been the tradition to target the enzymatic functions of HDAC
molecules for decades, but we want to bring attention to the non-enzymatic functions that should be targeted instead," Nguyen said. "In the words of Confucius himself, who introduced the Yin and Yang system of philosophy,
'Do not use a cannon to kill a mosquito,' as it might do more damage
than good." Presently, the findings of this study may also have some implications for treating COVID-19, as some of the patients with it
appear to suffer from septic-like conditions.

"The toxin used in this study produces an inflammatory 'cytokine storm,'
very similar to what has been seen in severe COVID-19 infections,"
Lazar said. "If a human cytokine storm is like the mouse, our research
suggests that targeting the HDAC3 protein rather than its enzyme activity
might mitigate the lethality of the virus." Co-authors on the study
include, Marine Adlanmerini and Amy K. Hauck, both from the University
of Pennsylvania.

Funding for the study was provided by the National Institute of Diabetes
and Digestive and Kidney Diseases (R37-DK43806) and the JPB Foundation.


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


========================================================================== Journal Reference:
1. Hoang C. B. Nguyen, Marine Adlanmerini, Amy K. Hauck, Mitchell
A. Lazar.

Dichotomous engagement of HDAC3 activity governs inflammatory
responses.

Nature, 2020; DOI: 10.1038/s41586-020-2576-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200805124050.htm

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