May 21st, 2024
Written by: Catrina Hacker
Your body is constantly engaged in a battle to keep you healthy. Leading the fight is your immune system, a collection of cells whose job is to protect you from foreign invaders that threaten the careful balance of cellular processes whirring away within your body. When the immune system sends its army of disease-fighting cells to the site of an attack, it results in a phenomenon known as inflammation1. When you think of inflammation you might picture a swollen ankle, but it can happen anywhere in your body if immune cells are active and flooding to the scene.
While inflammation is usually a good sign that your immune system is actively protecting you, it must be carefully balanced to be effective. If your cellular army attacks too hard, too much inflammation can harm your body. On the other hand, if it doesn’t attack hard enough, then it risks letting the foreign invader through to wreak havoc on your body. For a long time, scientists have suspected that the brain helps to maintain this balance. But exactly how the brain does this has long remained a mystery. This month, a group of researchers announced that they think they’ve finally found the neurons turning the dial up and down on inflammation.
The brain-body connection
A lot of neuroscience research focuses on the central structures of your nervous system, the brain and spinal cord, and how they’re used to interact with the world. However, your nervous system also consists of many nerves that snake throughout your body to connect it back to these important structures and keep it functioning properly. One of the biggest advances in neuroscience over the last decade has been an increasing appreciation for just how important these brain-body connections are for your overall health. Recently, a lot of excitement has centered around the vagus nerve, which connects your brain to other organs such as the heart and digestive system*2.
Given its important role in connecting the brain to the rest of the body, it’s perhaps no surprise that the vagus nerve may also be the connection between the brain and the body’s immune response3. However, until recently, neuroscientists didn’t know what neurons in the brain facilitated this communication and exactly which cells within the vagus nerve carried these messages to the body. This is important because if neuroscientists can find the neurons that maintain the balance between too much and too little inflammation, then maybe they can learn how to manipulate that dial to treat diseases where the body’s regulation of inflammation is broken, like long COVID or autoimmune diseases. That’s where this new study comes in.
*Because of this direct link from gut to brain, lots of new research is lending support to the age-old adage “you are what you eat”, with emerging links between gut health and diseases like Parkinson’s4.
Pinpointing the neurons that control inflammation
To answer this question, a group of researchers began by looking for the neurons that are activated when the body initiates an immune response5. To do this, they injected mice with a substance that triggers an immune response and searched the brain for neurons that became active. The researchers found a group of immune-activated neurons in a part of the brainstem that connects to the vagus nerve, called the caudal Nucleus of the Solitary Tract (cNST).
Now that they found a group of neurons they thought might be controlling the body’s immune response via the vagus nerve, they needed to prove it. To do this, they conducted a set of experiments where they either silenced or activated the cNST and measured how the body’s immune response changed. When they silenced the cNST it caused inflammation to run out of control, while activating the cNST reduced the amount of inflammation in the mice’s bodies. In other words, the cNST acts like a dial, maintaining the balance of the body’s immune response. When the dial is turned up it prevents inflammation whereas when it is turned down it increases inflammation.
But how do cNST neurons get information about inflammation in the body to know whether to turn the dial up or down? To figure this out, the researchers reasoned that because the vagus nerve connects the cNST to the body, it probably contains cells that tell the cNST whether to increase or decrease inflammation. To test this, they measured the activity of the vagus nerve in response to molecules that promote inflammation and molecules that prevent inflammation. In agreement with their idea, they found two non-overlapping groups of neurons in the vagus nerve: one that responded to substances that promote inflammation and another that responded to substances that prevent inflammation. When they activated the neurons that responded to substances that prevent inflammation, the cNST neurons were activated, and inflammation decreased.
Putting this all together, neurons in the vagus nerve convey information from the body to the brain about whether to increase or decrease inflammation. The cNST neurons that receive this information then act as a dial, turning inflammation up or down based on the signals they get from the vagus nerve.
From the lab to treating patients with immune disorders
This research is not only an exciting step forward in our understanding of how the brain and body communicate, but it also opens the door to a new avenue of treatments for patients with immune disorders. Many diseases are associated with an imbalance in inflammation, ranging from autoimmune disorders like multiple sclerosis, rheumatoid arthritis, celiac disease, and autoimmune encephalitis6, to Alzheimer’s Disease7 and long COVID8. A treatment that precisely targets the communication between the brain and immune system could have hugely positive impacts on millions of patients.
There’s still a long way to go before these findings in mice can be turned into treatments available to patients, but the researchers included exciting preliminary proof that vagus nerve neurons could be a good target for future treatments for immune disorders. Specifically, they found that mice with a condition that mimics ulcerative colitis, a disease characterized by high levels of inflammation in the intestines, had reduced symptoms when the anti-inflammatory vagus nerve neurons were activated5. This is exciting because it suggests that stimulating anti-inflammatory neurons in the vagus nerve could one day help treat diseases associated with increased inflammation.
References
1. Definition of inflammation – NCI Dictionary of Cancer Terms – NCI. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/inflammation (2011).
2. Breit, S., Kupferberg, A., Rogler, G. & Hasler, G. Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders. Front. Psychiatry 9, 44 (2018).
3. Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic in¯ammatory response to endotoxin. 405, (2000).
4. Dinan, T. G. Gut Feelings on Parkinson’s and Depression. (2017).
5. Jin, H., Li, M., Jeong, E., Castro-Martinez, F. & Zuker, C. S. A body–brain circuit that regulates body inflammatory responses. Nature (2024) doi:10.1038/s41586-024-07469-y.
6. Autoimmune disorders Information | Mount Sinai – New York. Mount Sinai Health System https://www.mountsinai.org/health-library/diseases-conditions/autoimmune-disorders.
7. Kinney, J. W. et al. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. Transl. Res. Clin. Interv. 4, 575–590 (2018).
8. Woodruff, M. C. et al. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat. Commun. 14, 4201 (2023).
Cover Photo by Moja Msanii on Unsplash
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