There are many ways that the human body responds to stress, from the adrenaline rush of the “fight-or-flight” instinct to more subtle, complex changes that may not be immediately recognizable to us.
New research shows that the actions of white blood cells called neutrophils are key not just to the body’s immune response but also its reaction to stress, and may explain psychiatric conditions such as post-traumatic stress disorder and depression.
The process starts with inflammation, the body’s response to stressors such as injury or infection, and what it does to the brain. “People have known for a long time that when there is inflammation, your brain changes,” said Emeka Okeke, an immunologist and assistant professor of biology at Northeastern University.
Inflammation in the brain has also been implicated in several diseases, including Alzheimer’s disease, Parkinson’s disease, and major depressive disorder, and so Okeke wanted to explore the relationship among neutrophils, inflammation, and stress-related psychiatric conditions.
“We are showing that the products released by neutrophils could actually damage the brain, the blood-brain barrier, and will promote inflammation in the brain,” he said.
Neutrophils are the most abundant type of white blood cell and are like first responders deployed to any site of infection or injury. There, these cells release substances including reactive oxygen species, enzymes, and cytokines to promote inflammation, which signals to the immune system to deputize other parts of itself to fight whatever the body is dealing with.
Among these substances are also neutrophil extracellular traps, or NETs, which Okeke describes as “like Spider-Man webs” that envelop pathogens.
Recent studies have found that neutrophils also release NETs when the body responds to chronic stress, Okeke said.
And while NET production is usually a good thing, there is a fine line between beneficial and problematic.
“When neutrophils produce these NETs, their primary role is supposed to be to engulf the pathogen,” explained Northeastern Ph.D. student Helder Price, who worked on the research. “But too much NET production can cause tissue damage if the NETs attach to tissue cells.”
“If stress activates neutrophils to release these NET products, the NETs could damage the blood-brain barrier” that protects the brain and nervous system from toxins and pathogens, Okeke said. Damage to that membrane could lead to inflammation in the central nervous system, which in turn could promote behavioral changes in stress-associated diseases like post-traumatic stress disorder and major depressive disorder, he said.
To better understand the mechanisms at play, Okeke tested “anxiety-like behavior” in a group of mice, half of which had been injected with NETs.
Compared to mice in the control group—which were curious and explored their open-air but contained surroundings—the mice that had been injected would not explore their surroundings, staying at the boundaries. The difference suggests, for the first time, according to Okeke, how NETs might be inducing behavioral changes in rodents.
However, the NETs weren’t working alone. The research also found that the production of NETs released stress hormones like cortisol. Okeke called it a “feed-forward loop,” by which neutrophils and stress hormones continuously amplify each other’s activity, ultimately altering brain function and resulting in behavioral changes.
To project how the findings might translate to humans, Okeke’s team analyzed blood samples of patients with major depressive disorder from a public database of gene expression and other data. Researchers found that genes linked to the formation of NETs were more active in people with clinical depression compared to healthy individuals.
Okeke said that he hopes to further explore the function of NETs by using MRIs to visualize how NETs disrupt the blood-brain barrier. He also sees neutrophils and NETs as potential pharmaceutical targets for treating depression and other stress-related psychiatric diseases.
“If we are actually able to specifically target these NETs in psychiatric diseases, that could be a new way to transform clinical care for patients with major depressive disorder and other stress-related diseases,” Okeke said.