Your Immune System Is Secretly Steering Your Emotions – New Research Reveals How

Two major studies from Harvard and MIT uncover a surprising link between the immune system and the brain, revealing how molecules released during inflammation can influence mood, anxiety, and even social behavior.

These immune messengers, once thought to act mostly outside the brain, are now shown to interact directly with specific brain cells. This research could unlock new treatments for autism and anxiety by targeting immune responses instead of the brain itself.

Mood Shifts After Illness: A Long-Observed Mystery

Doctors have long noticed a puzzling pattern: after an infection or a flare-up of an autoimmune disease, some people experience lasting mood swings, emotional instability, or changes in behavior. While the link between inflammation and mental health has been suspected for years, the biological mechanisms behind it have remained unclear.

Now, two new studies from Harvard Medical School and the Massachusetts Institute of Technology, published on April 7 in Cell, reveal how the immune system communicates with the brain to influence emotions and behavior.

Conducted in mice and partially funded by the National Institutes of Health, the research identifies specific molecular pathways involved in this brain-immune interaction. It shows that immune molecules known as cytokines can directly affect brain activity.

Cytokines’ Surprising Role in Emotions

Although scientists already knew that cytokines could influence emotions, it wasn’t clear exactly how or where this happened in the brain. These new findings map out a signaling network in which cytokines interact with specific brain cells involved in regulating mood, anxiety, and social behavior.

If confirmed in further studies in animals and people, these findings could lead to new therapies for autism and anxiety disorders. These treatments would work indirectly by altering immune chemicals to calm the immune system rather than by acting directly on the brain like traditional psychiatric drugs do. Those drugs must cross the protective blood-brain barrier to change brain chemistry directly, while the new approaches could work by adjusting immune signals from outside the brain.

“Identifying where and how cytokine receptors work in the brain, we have begun to unravel the complex relationship between the nervous and immune systems in the effect of this complex crosstalk on mood and behavior,” said Jun Huh, associate professor of immunology in the Blavatnik Institute at HMS and co-senior author on the two studies. “We hope these insights could eventually lead to new treatments for conditions like autism and anxiety disorders.”

Exploring the Brain’s Fear Center

In one study, the researchers found that cytokines act as brain messengers to regulate anxiety by targeting specific neurons in the brain’s fear center, an area called the amygdala, involved in processing emotions such as fear and stress.

Experiments in mice showed that two cytokines, IL-17A and IL-17C, increased activity in the amygdala. When levels of these molecules rose, mice exhibited corresponding increases in anxiety-like behaviors, such as avoiding open spaces and reducing exploration.

Surprisingly, blocking the receptor for cytokine IL-17A triggered an increase in IL-17A and IL-17C levels, amplifying amygdalar activity and worsening anxiety behaviors. Conversely, an anti-inflammatory cytokine, IL-10, had the opposite effect, calming the neurons of the amygdala and reducing anxiety. These findings suggest that inflammation-driven and anti-inflammatory signals interact directly with brain cells to shape mood and behavior.

Social Behavior Enhanced by Immune Signals

In the other study, researchers found that certain cytokines — IL-17A, IL-17B, IL-17E, and IL-17F — enhance social behavior in mice with autism-like traits. Normally, these mice show reduced social interest, but when given these cytokines, they became more engaged with other mice and displayed fewer repetitive behaviors.

IL-17E emerged as a key player, binding to specific brain receptors to promote social interaction. In mice displaying autism-like behaviors, the cytokine IL-17A appeared to boost IL-17E levels and thus enhance social behavior indirectly. In a surprising twist, the team also discovered that IL-17E is produced by neurons within the brain itself, challenging previous assumptions and opening new avenues for research.

A Neuromodulator Hidden in Plain Sight

Given that IL-17E is made by neurons themselves and capable of directly altering their activity, the researchers said, it may function as a neuromodulator, similar to two other brain chemicals — serotonin and dopamine. Serotonin is known as the “feel-good” neurotransmitter and is linked to relaxation, while dopamine plays a role in motivation and pleasure. This could help explain the results of earlier research by the same team showing that fever-induced inflammation might alleviate certain symptoms observed in some children with autism.

Taken together, the findings of the two studies underscore the intricate and powerful crosstalk between the brain and the immune system, the research team noted.

“Broadly, our results highlight the important role of immune signaling in shaping moods and behaviors by acting on specific brain pathways,” said co-senior author Gloria Choi, associate professor in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT.

Open Questions and Future Research

The findings of the two new studies mark a significant step forward in understanding brain-immune crosstalk, but key questions remain. Most notably, whether and how these mechanisms apply to humans.

Another lingering unknown: How do cytokines cross the blood-brain barrier, which typically shields the brain from harmful substances in the bloodstream? One theory is that chronic inflammation weakens this barrier, making it more permeable — an area ripe for further research.

If researchers can alter cytokines to regulate mood and social behavior, the approach could offer an appealing treatment alternative for anxiety disorders and autism-related conditions.

Explore Further: The Immune Molecule That Rewires Your Brain – From Anxiety to Sociability

References:

“Inflammatory and anti-inflammatory cytokines bidirectionally modulate amygdala circuits regulating anxiety” by Byeongjun Lee, Jeong-Tae Kwon, Yire Jeong, Hannah Caris, Dongsun Oh, Mengyang Feng, Irene Davila Mejia, Xiaoying Zhang, Tomoe Ishikawa, Brianna R. Watson, Jeffrey R. Moffitt, Kwanghun Chung, Jun R. Huh and Gloria B. Choi, 7 April 2025, Cell.
DOI: 10.1016/j.cell.2025.03.005

“Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB” by Yunjin Lee, Tomoe Ishikawa, Hyeseung Lee, Byeongjun Lee, Changhyeon Ryu, Irene Davila Mejia, Minjin Kim, Guangqing Lu, Yujin Hong, Mengyang Feng, Hyeyoon Shin, Sylvain Meloche, Richard M. Locksley, Ekaterina Koltsova, Sergei I. Grivennikov, Myriam Heiman, Gloria B. Choi and Jun R. Huh, 7 April 2025, Cell.
DOI: 10.1016/j.cell.2025.03.006

Additional authors on the two studies included Byeongjun Lee, Jeong-Tae Kwon, Yire Jeong, Hannah Caris, Dongsun Oh, Mengyang Feng, Irene Davila Mejia, Xiaoying Zhang, Tomoe Ishikawa, Brianna R. Watson, Jeffrey R. Moffitt, Kwanghun Chung, Yunjin Lee, Hyeseung Lee, Changhyeon Ryu, Minjin Kim, Guangqing Lu, Yujin Hong, Hyeyoon Shin, Sylvain Meloche, Richard M. Locksley, Ekaterina Koltsova, Sergei I. Grivennikov, and Myriam Heiman.

The two studies were supported by NIH grants 5P30EY012196, R01-MH115037, R01-MH119459, R01-CA227629, and R01-CA218133; the Jeongho Kim and the Brain Impact Foundation Neuro-Immune Fund; Young Soo Perry and Karen Ha; the Simons Center for the Social Brain; the Simons Foundation Autism Research Initiative; The Marcus Foundation; N of One: Autism Research Foundation; the Burroughs Wellcome Fund; a Simons Center for the Social Brain Postdoctoral Fellowship; a JSPS Overseas Research Fellowship; a Yamada Science Foundation Overseas Research Fellowship; a Harvard Brain Science Initiative Postdoc Pioneers Grant; Barbara Picower; the Freedom Together Foundation; The Picower Institute for Learning and Memory; and the MIT John W. Jarve (1978) Seed Fund for Science Innovation.

Huh and Choi consult for CJ CheilJedang and Interon Laboratories. Huh is an advisor on the Samsung Bio Advisory Board.

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