Discovered: A “brain-body circuit” that turns inflammation up and down

“Some scientists refer to the immune system as the seventh sense,” says Dr. Hao Jin, a neuroimmunologist at the National Institute of Allergy and Infectious Diseases (NIAID).

It’s a comparison that anyone who’s ever had a common cold can appreciate. Much like our traditional senses help us perceive and interact with our external world, our immune system — a complex network of cells, tissues, and organs — helps us sense and respond to threats in our internal environment.

And, as we all know, it’s not always a pleasant experience. When bacteria or viruses invade our body, our immune system springs into action, releasing pro-inflammatory molecules that recruit immune cells to fight. This triggers familiar inflammatory symptoms like fever or swelling — all aimed at creating an inhospitable environment for the invaders. It’s a delicate balancing act: Too much inflammation can damage healthy tissues and lead to chronic autoimmune disorders, while too little can leave us vulnerable to infection and disease.

Scientists have made significant strides in understanding the immune cells and bodily responses that govern immunity. Yet, whether and how the brain regulates inflammation is unclear, even though there is robust evidence that inflammation does impact the brain. Now, Dr. Jin and his colleagues, including Dr. Charles Zuker, an eminent neurobiologist at Columbia University, ask, “How does the brain impact immunity?”

In May, they reported identifying groups of neurons in the brainstem they called the “rheostat” of the body-brain immune response: Turn it one way and inflammation goes up; turn it another and it goes down. This research, published in Nature, has huge implications for treating diseases that create an over-the-top inflammatory response, from diabetes to arthritis. The findings also reshape our understanding of the immune response: Instead of being a localized call to action, it seems a more distant governor is calling the shots.

Diving into the brain-body connection

Dr. Jin says that he and Dr. Zuker started by studying the neurobiology of mammalian taste, or how the chemicals that create a taste also activate specific neurons that drive behavior: keep eating or don’t keep eating. For example, the Zuker lab discovered that the neurons responsible for sour tastes also make mammals react negatively to these acidic flavors — a handy way to ensure you don’t ingest something like car acid. They began to see similarities between how the brain processes taste signals and how it responds to threats to the body’s immune system.

“We are obsessed with how different tastes communicate with the brain through specialized pathways,” says Dr. Jin. “We’ve spent years researching how the brain detects taste and nutrient signals — which are chemicals — and transforms them into behaviors and actions. Since the immune system also relies on chemicals, we wondered if we could use the same methods from studying taste to understand the brain’s role in regulating the immune response.”

The inflammation “rheostat” 

The researchers began by infecting mice with bacteria that induced an immune response. Then they compared the brain activity of these infected mice with a control group that received only a saline solution. They noticed a significant increase in neural activity within the brainstem, along the vagus nerve, a long nerve pathway connecting the brainstem to organs like the heart, lungs, stomach, and intestines.

Using a mix of chemical and genetic methods, they directly influenced this neural pathway. Blocking it led to uncontrolled inflammation, with pro-inflammatory molecules spiking over 300% compared to control mice that received the same bacterial injection but still had an intact connection to the vagus neurons. In contrast, artificially activating the neurons reduced pro-inflammatory chemicals by 70% compared to infected mice that didn’t receive the same intervention.

These experiments clearly showed that brainstem neurons could directly regulate the inflammatory response. Then, the researchers discovered there are two distinct groups of neurons within the vagus nerve: one responding to pro-inflammatory signals and the other to anti-inflammatory cues. Acting as a kind of balance, these neurons communicate with the brain, forming what researchers called a “biological rheostat,” like a finely tuned dial that controls the level of inflammation.

“The brain quickly understands the inflammatory response’s status by reading these two neural signal lines,” explains Dr. Jin. “Then, it guides the body towards the appropriate immune response.” 

For Dr. Jin, the findings make perfect sense in retrospect. “The brain regulates a wide range of our bodily functions, including metabolism, respiration, and more. There is no reason why the immune response would be the exception.”

Restoring the immune balance

A huge number of diseases trigger an overly active and prolonged inflammatory response, like diabetes, autoimmune disorders, arthritis, and even long COVID.

As part of the research, they tested whether manipulating the groups of vagus neurons could slow down a wild immune response. They used a drug to activate the neural circuit in mice with ulcerative colitis, an autoimmune disorder that causes chronic inflammation in the colon lining. Activating the anti-inflammatory vagal neurons significantly reduced the concentration of inflammatory cells and protected the mice from impacts like colon damage, a finding that Dr. Luke O’Neill, a biochemist at the School of Biochemistry and Immunology in Trinity College, Dublin describes as “very impressive.” 

“This research is potentially very important,” says Dr. O’Neill. “We already know that the vagus nerve had a role in limiting inflammation, but this study provided far more specific insights into which neurons are specifically at play.”

Dr. O’Neill notes that activating the circuit increased the bacterial load when the researchers infected mice with salmonella but not in the control animals. This result indicates that there is far more left to learn about the logic of how this body-brain link works.

Ongoing exploration

One limitation of this study is common to much of immunology and medicinal research: The subjects are mice, not humans. The mouse inflammatory response parallels ours in fundamental ways. But Dr. Jin points out that there are differences in the specific types of inflammatory cells and the potential speed of the response.

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“The brainstem neurons we identified have analogous counterparts in humans,” he says. “But we need to study whether the human versions of these cells play similar roles when it comes to regulating inflammation.” 

While they work on finding evidence in humans, there is plenty more to learn about this circuit in mice and people. 

“We’d love to learn more about the descending branch of this body-brain circuit,” adds Dr. Jin. “How do these brainstem neurons exert their control over the distant inflammatory response?” 

Dr. O’Neill agrees, adding that we need more research to understand how to precisely activate this brain-body connection. 

If we could target those circuits very precisely, then there’s great potential to block the inflammation response for many diseases.

Along with the obvious practical implications, Dr. Jin highlights other aspects of the study that are particularly satisfying.

“It is very rewarding to see that the brain responds to inflammatory signals of opposing meaning (pro- and anti-inflammatory chemicals), with different ‘lines’ of neurons — just like one line of neurons responds to tastes that are bitter, and another responds to tastes that are sweet.”