Immune proteins known as cytokines hold significant importance in the body’s defense mechanism against diseases, aiding in the regulation of inflammation and orchestrating the activities of other immune cells. An increasing compilation of data indicates that some of these proteins may also affect the brain, inducing behavioral modifications during periods of illness.
Recent investigations from MIT and Harvard Medical School, concentrating on a cytokine named IL-17, contribute to this growing body of research. The scientists discovered that IL-17 interacts with two separate brain areas — the amygdala and the somatosensory cortex — to produce two contrasting outcomes. Within the amygdala, IL-17 can provoke feelings of unease, whereas in the cortex, it fosters social behavior.
These discoveries imply that the immune and nervous systems are closely intertwined, according to Gloria Choi, an associate professor of brain and cognitive sciences, a member of MIT’s Picower Institute for Learning and Memory, and one of the leading authors of the investigations.
“When you are unwell, numerous alterations occur in your internal conditions, mood, and behavioral states, which goes beyond just feeling physically drained. It relates to the functioning of the brain,” she states.
Jun Huh, an associate professor of immunology at Harvard Medical School, also serves as a senior author for both articles that are published today in Cell. One of the studies was headed by Picower Institute Research Scientist Byeongjun Lee and former Picower Institute research scientist Jeong-Tae Kwon, while the other was led by postdoctoral researcher Yunjin Lee from Harvard Medical School and Picower Institute postdoc Tomoe Ishikawa.
Behavioral impacts
Years ago, Choi and Huh became intrigued by IL-17 when they discovered its role in a phenomenon referred to as the fever effect. Extensive studies concerning autistic children revealed that many of them experience a temporary reduction in behavioral symptoms during a fever.
In a 2019 examination on mice, Choi and Huh illustrated that during specific infections, IL-17 is released, leading to the suppression of a particular area of the brain’s cortex known as S1DZ. Overstimulation of neurons in this sector can result in autism-like behavioral traits in mice, including repetitive actions and diminished social interaction.
“This molecule became a crucial link connecting immune system activation, represented as a fever, to shifts in brain functionality and behavioral changes in the animals,” Choi remarks.
IL-17 exists in six variants, and there are five different receptors capable of binding to it. In their latest publications, the team aimed to map the receptors expressed in various regions of the brain. The mapping process uncovered that a couple of receptors, identified as IL-17RA and IL-17RB, are present in the cortex, including in the previously noted S1DZ region. These receptors are situated in a cluster of neurons that receive proprioceptive information and are involved in behavior regulation.
When an IL-17 form known as IL-17E attaches to these receptors, the neurons experience reduced excitability, resulting in the behavioral changes documented in the 2019 study.
“IL-17E, which we’ve established as essential for behavioral moderation, operates almost identically to a neuromodulator by promptly diminishing the excitability of these neurons,” Choi explains. “Thus, there exists an immune protein functioning as a neuromodulator in the brain, with its primary role being to modulate neuron excitability.”
Choi theorizes that IL-17 may have initially developed as a neuromodulator, which was later co-opted by the immune system to facilitate inflammation. This hypothesis aligns with earlier studies indicating that in the worm C. elegans, IL-17 does not engage in immune functions but instead affects neurons. Among its effects in worms, IL-17 encourages aggregation, which is a type of social interaction. Furthermore, in mammals, IL-17E is actually produced by neurons in the cortex, including S1DZ.
“There’s a possibility that several forms of IL-17 initially evolved primarily to function as neuromodulators in the brain, and subsequently were utilized by the immune system to act as immune regulators,” Choi remarks.
Inducing anxiety
In the other Cell study, the researchers investigated another brain region where IL-17 receptors were discovered — the amygdala. This almond-shaped structure is crucial in emotion processing, particularly fear and anxiety.
This research indicated that in an area identified as the basolateral amygdala (BLA), the IL-17RA and IL-17RE receptors, which function as a duo, are expressed in a specific group of neurons. When these receptors engage with IL-17A and IL-17C, the neurons become increasingly excitable, prompting heightened anxiety levels.
The researchers also uncovered that, unexpectedly, administering antibodies that block IL-17 receptors results in an actual increase in IL-17C present in the bloodstream. This observation could elucidate unforeseen results seen during a clinical trial of a drug targeting the IL-17-RA receptor for psoriasis treatment, especially regarding its potential negative effects on mental health.
“We propose that the upregulation of the IL-17 ligand observed in this patient group might influence the brain to provoke suicidal thoughts, while in animals, it results in an anxious phenotype,” Choi asserts.
During infections, such anxiety may serve a beneficial purpose by ensuring the afflicted individual maintains distance from others to prevent spreading the illness, Choi theorizes.
“Apart from its primary duty of combating pathogens, one of the immune system’s roles is to influence host behavior, protecting both the host itself and the community to which it belongs,” she explains. “One method employed by the immune system is to utilize cytokines, secreted factors, to communicate with the brain.”
The team discovered that the same BLA neurons harboring receptors for IL-17 also possess receptors for IL-10, a cytokine that curtails inflammation. This molecule counterbalances the excitability induced by IL-17, affording the body a mechanism to alleviate anxiety once it is no longer beneficial.
Unique behaviors
Collectively, the two studies indicate that the immune system, and even a single category of cytokines, can yield various effects in the brain.
“We now see different combinations of IL-17 receptors being expressed in varied neuronal populations across two different brain areas, regulating distinctly different behaviors. One effect is comparatively positive, enhancing social interactions, while the other is rather negative, eliciting anxious traits,” Choi explains.
Her laboratory is currently focused on further mapping the locations of IL-17 receptors, alongside the IL-17 molecules that connect to them, particularly in the S1DZ region. Ultimately, a deeper understanding of these neuro-immune interactions could assist researchers in designing new therapies for neurological disorders such as autism or depression.
“The fact that these molecules originate from the immune system provides us with a novel strategy to modulate brain function as a therapeutic means,” Choi concludes. “Rather than solely targeting the brain, can we explore the potential of influencing the immune system?”
The study received funding from several contributors: Jeongho Kim and the Brain Impact Foundation Neuro-Immune Fund, the Simons Foundation Autism Research Initiative, the Simons Center for the Social Brain, the Marcus Foundation, the N of One: Autism Research Foundation, the Burroughs Wellcome Fund, the Picower Institute Innovation Fund, the MIT John W. Jarve Seed Fund for Science Innovation, Young Soo Perry and Karen Ha, and the National Institutes of Health.