The Brainstem Fine-Tunes Inflammation Throughout the Body

    

Last month, researchers discovered cells in the brainstem that regulate inflammation throughout the body. In response to an injury, these nerve cells not only sense inflammatory molecules, but also dial their circulating levels up and down to keep infections from harming healthy tissues. The discovery adds control of the immune system to the brainstem’s core functions — a list that also includes monitoring heart rate, breathing and aspects of taste — and suggests new potential targets for treating inflammatory disorders like arthritis and inflammatory bowel disease.

During an intense workout or high-stakes exam, your brain can sense the spike in your heart rate and help restore a normal rhythm. Likewise, the brain can help stabilize your blood pressure by triggering chemical signals that widen or constrict blood vessels. Such feats often go unnoticed, but they illustrate a fundamental concept of physiology known as homeostasis — the capacity of organisms to keep their internal systems working smoothly and stably amid shifting circumstances.

Now, in a paper published on May 1 in Nature, researchers describe how homeostatic control extends even to the sprawl of cells and tissues that comprise our immune system.

The team applied a clever genetic approach in mice to identify cells in the brainstem that adjust immune reactions to pathogens and other outside triggers. These neurons operate like a “volume controller” that keeps the animals’ inflammatory responses within a physiological range, said paper author Hao Jin, a neuroimmunologist at the National Institute of Allergy and Infectious Diseases.

The discovery may come as a surprise to immunologists who assume that the strength of an immune response is governed by the immune system’s own set of regulatory mechanisms, said a immunobiologist  who was not involved in the study. “We’ve never suspected that there will be something else on top of it, that we need an additional control. But clearly we do,” he said. “That’s what this work revealed: There are parts of the brainstem dedicated to this control.”

Perhaps it took a change in perspective to make the discovery. The new research doesn’t come from a traditional immunology lab but from one dedicated to the study of taste.

A Taste for Homeostasis

For as long as he can remember, the Chilean neurobiologist Charles Zuker has been captivated by the senses. After an early stint studying specialized light-sensing cells in the eyes of fruit flies, he became intrigued by the mammalian taste system. He has spent more than 25 years probing how organisms discern sweet, sour and other tastes, and how they use those signals to guide their behaviors.

Some of these behaviors are hard-wired, said Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia University. When a sweet taste “hits the brain, the brain knows that this is good. When it gets a bitter signal, it knows it is bad,” he said. These signals “trigger predetermined actions and behaviors” — such as reaching for a second piece of cake or spitting out rotten fruit. In the 2000s, Zuker and his colleagues cloned the genes for receptors that detect sweet, bitter, umami, sour and salty tastes to work out how this wisdom gets carried out at the molecular level.

At the time, Jin was finishing his doctorate at the National University of Singapore, studying immune cell development in zebra fish and pondering a shift to a more challenging system for the next phase of his career. He joined Zuker’s lab to study the brain in 2011.

In 2020, Jin’s colleagues published a landmark paper that proved an unexpected connection between the brainstem and the body. They had engineered a mouse with no sugar receptors. This animal could not distinguish plain water from sugar water; it drank equally from both bottles. That much was expected. Yet in the same cage, 48 hours later, the sugar water was gone and the plain water untouched.

What happened? They found that the animal’s preference for sugar was not mediated exclusively by the taste system. Rather, its sugar craving derived from a neural pathway that started in the gut and extended into the brain. Even though the mouse could not taste that the water was sweet, cells in the gut sensed the sugar and sent signals along the vagus nerve — a superhighway connecting body to brain — that taught the animal to want more. These gut-brain signals had activated a cluster of nerve cells in the brainstem.

Even though the mice didn’t get the immediate feedback of taste, they “learned there is something in there that makes them feel good — and that is what they want,” Zuker said.

Over the years, scientists have used advances in molecular tools to fill in the details on some of the vagus nerve circuits that control key bodily functions. Studies led by Stephen Liberles, a cell biologist at Harvard Medical School, suggest that the vagus nerve has a few dozen types of sensory neurons. One measures the volume of air in the lungs and triggers muscles for exhalation. Another picks up changes in blood pressure. Others sense the stretch of the stomach during a meal and prompt a feeling of fullness. “The brain receives this dizzying array of stimuli and needs to sort out all these incoming signals to ensure that physiology is appropriately controlled,” Liberles said.

Such studies helped usher in a “transformation in the way we think about the brain,” Zuker said. Historically considered the seat of memory and emotion, the brain may devote far less energy to these higher-order functions than to monitoring the body’s organs, physiology and metabolism to maintain homeostasis. “Everyone in the lab began to think about that,” he said. “How far does the brain’s control over body biology go?”

However, the immune system wasn’t a part of their view of homeostasis — until Jin went back to his roots.

Tracking Immunity to the Brain

On first pass, our sense of taste and our immune system appear to have little in common. The former allows us to savor textures and flavors from different cuisines, while the latter protects us from germs. But at their essence, both are defense systems against foreign substances going into the body, Jin said: The taste system is the gateway for food and drink, while the immune system handles bacteria and viruses.

Research decades ago suggested that the vagus nerve controls inflammatory responses — pointing to a body-brain connection. Jin wondered if he could use genetic approaches in the Zuker lab’s mouse models to trace inflammatory responses in the brain. These methods allow scientists to target never cells with high precision “so we can not just identify but also access and manipulate those neurons that respond to inflammation,” Jin said. “We can change their activity to study their function.”

He injected mice with a substance that mimics an infection and then scanned their brains to see which regions activated. Curiously, many of the activated neurons were located in the same area of the brainstem that lit up in the mice that couldn’t taste sugar.

He and his colleagues wanted to figure out which brain circuits were involved. In one experiment, they cut the vagus nerve and saw that, without its input, the brainstem neurons remained inert — demonstrating the vagus nerve’s central role in this brain-body immune circuit. Then they used genetic techniques to dial the brainstem neurons’ activity up or down. When dialed down, the mice experienced an out-of-control inflammatory response, with a corresponding rise in pro-inflammatory molecules and a dip in anti-inflammatory molecules. Dialing up the brainstem cells’ activity did the opposite: Anti-inflammatory molecules shot up, while levels of pro-inflammatory molecules plummeted, putting a damper on inflammation.

The findings raise intriguing questions, Liberles said. For example: What other cells and circuits partner with these neurons to regulate immune reactions? Are there additional central controllers in the nervous system? There may be “multiple highways of communication” between the brain and the immune system, he said.

“The big question is what aspects of the internal state are actively monitored by specialized neuronal circuits,” Medzhitov wrote in an email. “We knew about some of them for a while (heart rate, blood pressure, blood oxygen, etc.). But we are now learning that the inflammatory state and immunity are also somehow monitored and actively controlled by the brain.”

Perhaps the most exciting part of the discovery is its implications for medicine. In a final set of experiments, the team showed that, in mice, activating the vagal-brainstem circuit could restore immune balance and prevent inflammatory states resembling ulcerative colitis and sepsis. This suggests potential new strategies for treating conditions such as rheumatoid arthritis, inflammatory bowel disease, Type 1 diabetes and other inflammatory disorders, Zuker said.

Similar mechanisms likely exist in people, Liberles said. In mice and humans, “the general blueprints for how the sensory systems work are actually quite similar.” The eventual goal would be to design a way to control these immune-balancing circuits in people to tamp down inflammation in specific organs or diseases. “That would be the dream,” he said, “and I think it’s possible.”

 

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