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Physicians have long observed a mystifying phenomenon: After a bout of infection or an autoimmune disease flare-up, some people experience prolonged mood swings, emotional dysregulation, and changes in behavior. But the precise connection between inflammation, mood, and behavior has remained elusive.
Now, two new studies from Harvard Medical School and Massachusetts Institute of Technology, published April 7 in Cell, detail the steps of an intricate brain-immune crosstalk that accounts for this long-known but poorly understood observation.
The work, conducted in mice and funded in part by the National Institutes of Health, pinpoints the molecular roots of the phenomenon and shows how immune molecules called cytokines influence brain activity.
Scientists already knew that cytokines affect emotions and brain function, but how and where in the brain this occurs has thus far remained unclear. The new research maps a network of cytokine signals that interact with specific brain cells to regulate 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.”
Immune molecules alter response in 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.
Immune molecules precision-target specific brain receptors
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.
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.
Unanswered questions and next steps
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.
Authorship, funding, disclosures
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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