As of 2021, over 3.4 billion people—or about 43% of the world’s population—suffer from some form of neurological disorder. Many such diseases are also associated with higher risks of developing other mental conditions.
In 2023, Duke University researchers in the Filiano Lab linked the continuous activity of several immune signaling enzymes to neurological diseases, including autism and schizophrenia. This research represents a compelling step towards understanding the cause of neurological disorders, which remain largely unknown.
The Filiano Lab is dedicated to understanding the interactions between the immune system and the nervous system, as well as the development of cell therapies to treat diseases of the central nervous system (CNS). Dr. Anthony Filiano has studied neuroinflammation and CNS diseases since he was an undergraduate. Though he initially wanted to become a medical doctor, a lab internship changed his course, causing him to shift his interests toward a career in research.
Dr. Filiano went on to work in several other neuroscience labs as a postdoctoral researcher, investigating models of neurological disorders in mice. While studying a mouse model of dementia, he found that the brains of affected mice experienced significant inflammation. He later helped publish findings indicating that cytokines, small proteins that act as messengers for the immune system, are integral for social behavior as well. He and his team hypothesized that these proteins might contribute to “diseases that have components of social behavior,” such as autism or attention-deficit hyperactivity disorder.
Meanwhile, other labs linked interferon-gamma (IFN-𝛾), a cytokine related to inflammation, to neurological disorders. Although IFN-𝛾 plays an important role in fighting viruses and tumors and is necessary to maintain a healthy nervous system, too much of it can have severe consequences in what Dr. Filiano calls a “Goldilocks effect.” Researchers observed high quantities of IFN-𝛾 associated proteins in people diagnosed with neurological diseases, indicating that excessive IFN-𝛾 must have been present at some point. However, such high levels of IFN-𝛾 itself were not detected. As such, the Filiano Lab was interested in understanding the long-term effects of the IFN-𝛾 cytokine on neural cells.
Above: Model of the interferon-gamma complex (IFN-𝛾). Image courtesy of SciencePhotoGallery.
For these experiments, the Filiano Lab cultured the neurons of mice and recorded the neurons’ response to various concentrations of IFN-𝛾. The team found that when compared to neurons given a dose of IFN-𝛾 that is seen in healthy neurons, neurons given excessive IFN-𝛾 saw prolonged effects: IFN-𝛾 regulated immune proteins were present in much larger quantities and remained at high levels for longer durations. The presence of these excess immune proteins can cause immune cells to activate and attack the region—even in the absence of infection—and can cause damage to neurons and the cells that support them.
For either dosage, the highest rate of production for IFN-𝛾 regulated proteins occurred right after IFN-𝛾 was removed, confirming that it was not directly responsible for this activity. Most likely, IFN-𝛾 activates some other substance that causes cells to produce more proteins even when IFN-𝛾 itself is absent. The researchers found that the substances responsible were Janus Kinases (JAK1 and JAK2), which are enzymes that act as an intermediary between IFN-𝛾 and the proteins it activates. When the enzymes were blocked, the effects of IFN-𝛾 were not observed, whereas the effects persisted when the JAKs were allowed to function. Therefore, the team concluded that the prolonged activation of these enzymes caused the persistent effects of IFN-𝛾. Future studies could focus on creating treatments that inhibit these enzymes in order to block the effects of IFN-𝛾.
The study also discovered that this process could change neurons’ genetic profile long-term. When sequencing genes from neurons that had been exposed to high quantities of IFN-𝛾, the Filiano Lab found that the RNA in these neurons not only differed from those that had received a standard dose of IFN-𝛾 but also varied greatly between neurons that received the same treatments, with as low as 26% similarity between their genome expressions. “If at some point in your life, [a neuron] sees this high level of IFN-𝛾… we think that it programs the neuron long-term,” Dr. Filiano said.
The Filiano Lab plans to continue studying the interface between the immune and nervous systems. The researchers recently published follow-up work, in which the team gave mice excessive IFN-𝛾 and observed symptoms of hyperactivity that would implicate neurodevelopmental disorders. Still, questions remain: Why do neurons have unique reactions to different IFN-𝛾 quantities, and how can researchers develop treatments to mitigate the effects of IFN-𝛾? Undoubtedly, the Filiano Lab will be at the forefront of this research in the coming years.