Finding a Master Immune System Controller | HHMI

"Almost everything known so far is that regulation lies within the immune system itself," explains Howard Hughes Medical Institute Investigator and immunologist Ruslan Medzhitov at Yale School of Medicine. "It was thought that's all there is—and there's been no reason to suspect something else."

No longer. In a series of groundbreaking, elegant experiments, published onlineexternal link, opens in a new tab on May 1, 2024, a team led by Howard Hughes Medical Institute Investigator Charles Zuker has found that one controller of the immune system actually lies elsewhere—in the brain. The researchers showed that a group of nerve cells in the brainstem acts like a master controller or rheostat, sending and receiving signals from vagal neurons in the body to either boost inflammation or dial it down. 

The discovery "is very surprising and exciting," says Medzhitov, who was not involved in the new research. "It opens up a new way of thinking and a whole new direction of research." Perhaps even more important to humanity, it flings wide open a new door to designing radically different strategies for tackling diseases involving the immune system. "I've been fortunate to have been part of some meaningful discoveries, but this is a unique case where the connection between basic science and human disease is so promising," says Zuker, a professor of biochemistry and neuroscience at Columbia University.

Zuker's lab was uniquely positioned to make this scientific leap. Zuker's previous research focused on the brain's role in creating people's insatiable appetite for sugar and fat. His group's work revealed that the vagus nerve, which runs from the brain to areas around the intestines, the so-called gut-brain axis, provides the key highway for carrying sugar and fat signals between brain and body. Meanwhile, it was also well established that a brain-body connection through the vagal nerve system controls other vital functions, like digestion, heart rate and lung function.

The first big question for Zuker's group, therefore, was whether the brain really does respond to signals from the immune system. To find out, his team injected mice with a known immune stimulant, lipopolysaccharide, then searched the mouse brain to see if any specific areas were being activated by the signal. The quest was like "looking for a needle in a haystack," says Medzhitov. But it worked. The researchers pinpointed an area of the brainstem called the caudal nucleus of the solitary tract. That was "extraordinarily exciting," recalls Hao Jin, a postdoctoral fellow in Zuker's lab who led these studies. Previous work by Zuker's team had shown that this area of the brain received other body-brain signals up the vagus nerve highway.

But were those brainstem neurons sending—as well as receiving—signals? They addressed the question with cutting-edge genetic engineering techniques. They used a viral vector to slip new receptors into the neurons that could act like a switch. Using chemicals that bound to the receptors, the researchers could thus turn the neurons on and off. "That gave them almost magical power over the system," says Medzhitov.

In one key experiment, the team gave mice immune stimulants while turning off the brain neurons. The animals quickly developed a massive, runaway immune reaction, much like the extreme dysregulated immune response underlying deadly sepsis or a cytokine storm in humans. But when the scientists activated the brain stem neurons at the same time as the stimulant doses, the animals' immune systems mounted a rapid and strong anti-inflammatory response—and almost all those mice survived. Moreover, the researchers could control different parts of this body-brain neural circuit, and depending on the signals the brain receives, it either ramps up inflammation or tones it down. 

Zuker's team didn't stop there. They also probed the vagal nerve system for clues about its role in the control of the immune system. "Much to our surprise and delight," says Mengtong Li, another postdoctoral fellow in Zuker's lab who co-authored the study, they found two distinct populations of vagal neurons. One carries the pro-inflammation signals to the brain; and the other carries the anti-inflammation signals, thus together they inform the brain of the inflammatory state. 

Scientists say that new findings will have profound implications for both basic science and clinical applications. "They immediately make you think of new and really interesting questions to ask," says Medzhitov, such as how signals are carried back and forth from the immune system to the brain, and how the master controller system might go awry in many diseases and disorders, including cases of out-of-control inflammation. And for those suffering from immune system disorders, the discoveries offer potential pathways for medications that could precisely turn the dial on the master controller up or down as needed to correct the dysfunction. "This could help change the way we think managing a number of immune disorders and diseases," says Hao Jin.

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Citation

Jin, H., Li, M., Jeong, E. et al. A body-brain circuit that regulates body inflammatory responses. Nature (2024). https://doi.org/10.1038/s41586-024-07469-yexternal link, opens in a new tab