One Molecule May Orchestrate the Yin-Yang of Inflammation

Last year, an international group of scientists from over two dozen institutions around the globe published a comprehensive perspective (Furman et al., 2019) on the heavy toll that chronic inflammation can take on someone's psychological and physical well-being across the lifespan.

It's important to note that there are two types of inflammation: First, there is acute inflammation, which should only last for a few hours or days. Second, there is chronic inflammation, which lasts for weeks, months, and even years. Although many people mistakenly assume that "all inflammation is bad," when the acute inflammatory response is well-orchestrated and swift, it's a lifesaver.

Perfectly orchestrated inflammatory responses trigger temporary swelling and increase blood flow, which allows white blood cells to protect and rid one's body of harmful invaders. A well-orchestrated inflammatory response quickly and precisely zeroes in on an area of injury or infection. Ideally, after mitigating the threat of a virus or bacteria, the inflammatory response switches over to an anti-inflammatory process that reduces swelling and removes damaged tissue so healing can begin.

Unfortunately, in some cases, for reasons that remain unclear, the orchestration of some patient's acute inflammatory response is more analogous to the mechanisms associated with dissonance and cacophony than a finely-tuned, harmonious symphony.

As an example, uncontrollable "cytokine storms" marked by a hyperactive inflammatory response have been widely reported in patients with COVID-19. Long before this coronavirus public health crisis, too much inflammation was seen as the hallmark of inflammatory cytokine storms that could lead to things like septic shock and organ failure.

Yet the million-dollar question has proven difficult to answer: What causes the rise and fall of inflammatory factors to perform flawlessly in some patients and to go haywire and cause a cytokine storm in other cases?

This week, researchers from the University of Pennsylvania published new research that identifies how a molecule called histone deacetylase 3 (HDAC3) appears to orchestrate the immune system's inflammatory responses to infection in a dichotomous way and helps to explain the molecular mechanisms behind cytokine storms in mice. This paper (Nguyen et al., 2020) was published on Aug. 5 in the journal Nature.

Notably, the Perelman School of Medicine scientists found that HDAC3 appears to be directly involved both in producing agents that kill harmful pathogens and in restoring homeostasis. According to the authors, these findings suggest that HDAC3 may be "a molecular mechanism that helps the body mount perfectly balanced responses to deadly infections."

Source: Gordon Johnson/Pixabay

"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," senior author Mitchell Lazar said in a news release. "Now that we understand this, it is much clearer what needs to be targeted when medications are tested and used to counter potentially deadly inflammation." Lazar is director of the Institute for Diabetes, Obesity, and Metabolism (IDOM) and founder of Penn's Lazar Lab.

Until now, most HDAC3 research has focused on how this molecule functions as an enzyme. This new research used "multiple advanced genomic technologies" in a mouse model to isolate and identify how HDAC3 switches between different enzymatic states. The dichotomous ability of HDAC3 activity to govern inflammation by activating or repressing the inflammatory response gives this molecule what the researchers call "a yin and yang type of existence."

"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," first author Hoang C. B. Nguyen said in the news release. "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." Nguyen is currently a Penn medical student and Ph.D. candidate in Lazar's Lab.

"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," Nguyen added. "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."

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"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."

The latest HDAC3 findings (2020) by Nguyen et al. could have implications for how doctors treat COVID-19 in the future. From a pharmaceutical perspective, these findings could also inform how HDAC inhibitors are used to fight against other diseases such as cancer and may lead to new treatments that counteract chronic systemic inflammation.