Scientists have uncovered new evidence that depression could be linked to immune cells moving from the skull into the protective layer of the brain.
The findings, published in Nature Communications, suggest that the immune system—not just brain chemistry—may play an important role in depression and anxiety.
This could eventually lead to new treatments for people who do not respond to traditional antidepressants.
Depression and anxiety affect around one billion people worldwide.
While the causes are complex, researchers have increasingly focused on inflammation, a state in which the body’s immune system stays switched on even when there is no infection or injury.
Chronic inflammation has been tied to a higher risk of mood disorders, but exactly how it influences the brain has been unclear.
One type of immune cell, called the neutrophil, has drawn attention. Neutrophils are white blood cells that act as the body’s “first responders,” rushing to sites of infection or injury.
Previous studies have shown that higher levels of neutrophils are linked to worse symptoms of depression. But what these cells were doing inside the brain was not well understood.
A team of researchers from the University of Cambridge in the UK and the U.S. National Institute of Mental Health explored this question using a mouse model of chronic stress.
They exposed mice to repeated stressful encounters with aggressive “resident” mice. Over time, this social stress led to clear signs of depression-like behavior.
When the scientists examined the brains of these stressed mice, they found high numbers of neutrophils in the meninges—the thin membranes that cover the brain and spinal cord.
What made the discovery more striking was that these neutrophils appeared to come directly from the bone marrow in the skull, rather than from elsewhere in the body. Even after the stressful conditions ended, the neutrophils remained in the meninges for longer than they stayed in the blood.
This persistence may explain why the effects of stress can linger, contributing to ongoing symptoms of depression.
The researchers also found that these neutrophils showed signs of “type I interferon signaling,” a kind of immune system alarm.
When they blocked this pathway, neutrophil numbers in the meninges dropped and the mice’s behavior improved. This is important because interferons are already known to affect mood. Patients receiving interferon treatments for hepatitis C, for example, sometimes develop severe depression as a side effect.
Why neutrophils accumulate in the meninges is not yet clear. One possibility is that they are summoned by microglia, the brain’s own resident immune cells. Another idea is that chronic stress may cause tiny leaks in blood vessels in the brain, drawing neutrophils to repair the damage. But once there, they may become rigid and stuck, fueling further inflammation.
Dr. Stacey Kigar from the University of Cambridge explained that these findings help reveal how chronic stress reshapes the brain’s immune environment.
“Our work shows how immune cells in the skull may influence mood and behavior,” she said. Dr. Mary-Ellen Lynall, also at Cambridge, added that this research could help identify a biological “signature” of depression linked to inflammation. That in turn could allow doctors to match patients with new treatments targeting the immune system.
The results may also shed light on why depression is so common in people with other brain disorders, such as stroke or Alzheimer’s disease, where immune responses are triggered by damage to brain tissue. It may even explain why depression itself increases the risk of dementia later in life, if neutrophils directly contribute to injury in the brain.
For now, the research is limited to mice, but the discoveries open a new window into how the immune system and the brain interact.
If confirmed in people, it could lead to therapies that move beyond the traditional focus on brain chemicals to address the hidden role of the body’s immune defenses in mental health.
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Source: University of Cambridge.
