For Laszlo Nagy, M.D., Ph.D., the question was how? How does the body’s first line of defense against an inflammatory disease receive a signal to embark on long-term tissue regeneration and repair?

The Nagy Lab at Johns Hopkins All Children’s Hospital spends considerable time seeking to understand macrophages, which are white blood cells that play a key role in defending against disease. Macrophages help clear the body of bacteria, viruses, fungi and parasites, but an imbalance in macrophages can compromise the immune system and the response to inflammation. Past work shows that certain proteins send a signal to macrophages to initiate the repair response, but that signal does not last long. Nagy and his team set out to discover how the body signals the repairing macrophage to perform a longer-term response.

In an article published online and in the November 2020 edition of the journal Genes and Development, Nagy and his team reveal the “linchpin” that bridges the gap of that response. The team identified a “transcription factor” known as Early Growth Response 2 (EGR2), which triggers the long-term response. 

“The big picture is the more we understand about the wiring of the macrophage, the more we are able to push macrophages into the direction of repair instead of destroy,” says Nagy, co-director of the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research in St. Petersburg, Florida. “It’s an identification of a very important piece of the puzzle.”

The Aha Moment

The paper, “The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization,” outlines how Nagy and his collaborators mapped the epigenetic response through early and late stages and used data analysis to identify EGR2.

“We used these high throughput sequencing type approaches, so we really cast a very wide net,” Nagy says. “We asked what’s happening when we hit the cell with this repair-type macrophage polarizing factor, which is called interleukin-4. We looked at all the regions in the genome that open up because we thought when we find a factor that is mediating this polarizing effect, we just look at the sequence in the genome to see what the sequence is using computers and data and it picked up EGR2.”

Nagy compared the discovery process to finding a genetic footprint.

“We could have been wrong or there could have been five different factors that each contributed slightly, but this is such a robust factor that it was easy to find,” he says. 

Nagy is the senior author on the paper, but much of the writing was done by Bence Daniel, who was the American Heart Association postdoctoral fellow in the Nagy Lab from 2017-2019 and now is a postdoctoral fellow at Stanford. The study received funding from the National Institutes of Health.

What’s Next?

Nagy and his team are not currently studying COVID-19, but they are focusing on EGR2’s role in immune response of the lungs. Nagy believes EGR2 could one-day play a role in treating infectious diseases such as pneumonia, flu or a virus similar to COVID-19. He also believes it could help treat inflammation caused by smoking or vaping.

“We are studying EGR2 in multiple studies,” he says. “Before this, I didn’t even consider EGR2 an important thing to study.

“The key here is that it’s very important to understand how the immune system is harming or helping the body,” he says. “The immune system is a double-edge sword because people die of the over-reaction of the immune system, so you have to regulate it. If you over-regulate it, there’s no immune response and the pathogens will overgrow us, so we need to understand these switches. What turns on and off the immune cells.”