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Cytokines, crucial immune molecules, play significant roles in defending the body against infections. They are instrumental in regulating inflammation and orchestrating the actions of other immune cells. Recent research indicates that these molecules may also have profound effects on the brain, potentially influencing behavior during periods of illness.
New findings from studies conducted by researchers at MIT and Harvard Medical School center on a specific cytokine known as IL-17. The studies reveal that IL-17 engages with two separate areas of the brain—the amygdala and the somatosensory cortex—producing contrasting effects. In the amygdala, IL-17 is linked to increased anxiety, whereas in the cortex, it appears to foster sociability.
These discoveries point to a complex interaction between the immune system and the nervous system, according to Gloria Choi, an associate professor of brain and cognitive sciences and a senior author of the studies. “When you are unwell, various changes occur in your mental state and behavior, which go beyond mere physical fatigue. It involves brain activity,” she remarks.
Joining Choi in the research efforts is Jun Huh, an associate professor of immunology at Harvard Medical School. Their studies, published today in Cell, were led by various researchers from their institutions, including Byeongjun Lee and Jeong-Tae Kwon from the Picower Institute at MIT, and postdocs Yunjin Lee and Tomoe Ishikawa from Harvard Medical School.
Behavioral effects
Choi and Huh’s interest in IL-17 was piqued several years ago when they discovered its role in the fever effect, a phenomenon observed in children with autism, where fever temporarily alleviates certain behavioral symptoms.
In a previous experiment conducted on mice in 2019, the researchers demonstrated that during certain infections, IL-17 suppresses a specific brain area called S1DZ. Excessive neuron activity in this region can result in autism-like behaviors in mice, such as repetitive actions and reduced social interaction.
“We’ve established that this molecule links immune system activation, represented as fever, to altered brain function and behavior,” Choi explains.
IL-17 features six variants and five receptors that bind to it. The team aimed to identify where these receptors are expressed throughout the brain. This mapping confirmed the presence of two receptors, IL-17RA and IL-17RB, within the cortex, specifically in the S1DZ, which is associated with behavior control based on proprioceptive input.
Upon binding of IL-17E to these receptors, the activity of the neurons diminishes, correlating with the behavioral changes noted in their earlier study. Choi elaborates, “IL-17E, shown to be essential for behavioral mitigation, functions similarly to a neuromodulator by lowering neuronal excitability. This suggests the presence of an immune molecule that modulates brain function primarily by regulating neuron activity.”
Choi speculates that IL-17 may have initially developed as a neuromodulator before being utilized by the immune system for its inflammatory roles. This hypothesis aligns with earlier observations in C. elegans, where IL-17 does not contribute to immunity but rather influences neuronal behavior, including promoting social aggregation. Additionally, IL-17E is synthesized in cortical neurons, including those in S1DZ.
“It is plausible that some variants of IL-17 were first evolved to serve as neuromodulators and were subsequently repurposed by the immune system to function in immune modulation,” Choi suggests.
Provoking anxiety
The second study explored another brain region housing IL-17 receptors—the amygdala. This almond-shaped structure is crucial for emotion regulation, especially concerning fear and anxiety. Here, researchers noted that IL-17 receptors (IL-17RA and IL-17RB) are expressed in specific neuronal populations in the basolateral amygdala (BLA). Binding of IL-17A and IL-17C to these receptors enhances neuronal excitability, which heightens anxiety responses.
Interestingly, the research also found that blocking these IL-17 receptors led to increased levels of IL-17C in the bloodstream. This observation helps clarify some unexpected findings from clinical trials involving drugs targeting the IL-17-RA receptor for psoriasis, particularly regarding potential implications for mental health.
Choi hypothesizes that upregulated IL-17 in patients could have adverse effects on mental well-being, potentially inducing suicidal thoughts, a notion mirrored in animal models exhibiting anxiety-like traits. She postulates that such anxiety might serve a protective function during infections by encouraging social distancing to prevent disease spread.
“Apart from combating pathogens, the immune system influences host behavior to safeguard both the individual and their community. Cytokines serve as communication tools, transmitting signals from the immune system to the brain,” she adds.
Notably, the same neurons in the BLA that possess IL-17 receptors are also responsive to IL-10, another cytokine known to dampen inflammation. This interaction provides a regulatory mechanism for anxiety, allowing the body to diminish anxious responses when they are no longer necessary.
Distinctive behaviors
Collectively, the findings from these studies indicate that the immune system, even through a single family of cytokines, can influence various behaviors within the brain. “We are observing different receptor combinations of IL-17 in distinct neuron populations across two brain regions, each linked to significantly different behavioral outcomes—one promoting positive social interaction, while the other may induce anxiety,” Choi states.
Choi’s lab is committed to further mapping IL-17 receptor distribution and the IL-17 variants that interact with them, concentrating on the S1DZ area. This deeper understanding of neuro-immune connections might pave the way for innovative treatments aimed at neurological disorders, including autism and depression.
“Understanding that immune molecules can impact brain function opens up new therapeutic avenues. Instead of targeting the brain directly, we might consider how to influence the immune system to elicit beneficial brain responses,” concludes Choi.
The research received funding from various institutions, including the Brain Impact Foundation Neuro-Immune Fund, the Simons Foundation Autism Research Initiative, and the National Institutes of Health.
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