PHILADELPHIA—Researchers from the Perelman School of Medicine at the University of Pennsylvania have identified a protein called histone deacetylase 3 (HDAC3) as the orchestrator of the immune system’s inflammation response to infection. By using both 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 article, entitled “Dichotomous engagement of HDAC3 activity governs inflammatory responses,” was published in Nature. It shows that some of the methods which target molecules like HDAC3 could actually have unintended, and potentially 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,” explained senior author Mitchell A. Lazar, M.D., Ph.D., director of the Institute for Diabetes, Obesity, and Metabolism. “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.”
The innate immune system employs inflammation as a complex defense mechanism. Inflammation is famous for the appearance of swelling, but 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 which help with the removal of damaged tissues, so that the body can begin to heal and repair.
But the body’s inflammation response can also be damaging. When the rise and fall in inflammatory factors goes unchecked, diseases like cancer, heart disease and diabetes can develop. Too much inflammation can cause reactions like septic shock, which involves multiple organ failures within the body due to an uncontrolled cytokine storm. And cytokine storms are a phenomenon widely reported in patients infected with COVID-19.
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. 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 the inflammation response.
To test the enzyme’s function, 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, and observed high levels of protection against the infectious toxin. 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 their expectations. But in the third model, when HDAC3’s enzyme activities were completely blocked by replacing it with a mutant form of HDAC3, 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. 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,” pointed out the study’s lead author, Hoang C. B. Nguyen, an M.D./Ph.D. student in the Lazar Lab at the Perelman School of Medicine.
It’s important to note that this 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. The researchers hope that their work will inform pharmaceutical work. 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 noted. “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.”
“Although classically associated with transcriptional repression, a growing body of evidence suggests that HDAC3 might also function as a coactivator. Here we have demonstrated selective enzymatic engagement of HDAC3 as a function of its differential association with co-repressor complexes NCoR1 and NCoR2, selectively coordinated by either ATF3 or ATF2,” the article states. “Our results implicate HDAC3 as a critical integrator of pathogenic stimuli to orchestrate well-balanced inflammatory responses. Efforts to attenuate class I HDAC enzymatic activity for immunomodulation should carefully consider the paradoxical intensification of enzyme-independent, pro-inflammatory activities of HDAC3.”
The findings of the study could also have immediate implications for treating COVID-19, as some of the patients with the coronavirus 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 added. “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.”