Study Links Chronic Stress to Changes in Immune Cells and Depression

A recent study indicates that chronic stress may lead specific immune cells, known as neutrophils, to relocate from the skull’s bone marrow to the brain’s protective layers. This movement seems to be tied to depressive symptoms. Researchers found that by blocking an immune signaling pathway in mice, they could reduce the number of these cells and improve mood-related behaviors.

These findings shed light on how stress impacts brain immunity and provide insights into why a significant portion of patients may not respond to current antidepressants. It also suggests avenues for developing more personalized treatments and underscores the connection between depression and other neurological conditions, such as Alzheimer’s and stroke.

Key Findings

• Chronic stress prompts neutrophils from skull bone marrow to enter the brain’s protective membranes, which affects mood.
• The research identified an immune signaling pathway that, when blocked, resulted in fewer neutrophils and fewer depressive behaviors in mice.
• These results could lead to new treatments targeting the immune response for those who do not respond to standard antidepressants.

Research from the University of Cambridge highlights the role that chronic stress and inflammation may play in mental health. Specifically, it indicates that stress can drive neutrophils out of bone marrow and into the brain, potentially contributing to depression and anxiety symptoms.

Around one billion people are projected to experience a mood disorder, such as depression or anxiety, at some point in their lives. Chronic inflammation, where the immune system remains active without any clear infection, has been implicated in mood disorders, suggesting the immune system’s significant role in the development of these conditions.

Previous studies have noted a link between heightened neutrophil levels and the severity of depression. However, the mechanisms by which these cells influence depressive symptoms remain unclear.

This research, published in Nature Communications, tested the hypothesis that chronic stress leads to neutrophil release from the skull’s bone marrow. The team of scientists used a mouse model exposed to chronic social stress—where an aggressive mouse was placed in the territory of another mouse—leading to observable behavioral changes and increased neutrophil presence in the protective membranes around the brain.

After the stress was removed, the neutrophils remained longer in the brain membranes than in the bloodstream. The analysis suggested that these meningeal neutrophils were indeed originating from the skull.

The team also discovered that long-term stress activates a type of immune system alert known as type I interferon signaling in neutrophils. Blocking this alert reduced the neutrophil count in the meninges and alleviated depressive behaviors in the affected mice.

Dr. Stacey Kigar from the University of Cambridge emphasized that these findings clarify how chronic stress impacts the brain’s immune environment, potentially contributing to lasting mood changes. They also raise the possibility of new immune-targeted treatments that could benefit those who do not respond to traditional medications.

The reasons for the increased neutrophil presence in the meninges remain uncertain. One theory is that they could be recruited by microglia—brain-specific immune cells. Another possibility is that chronic stress might cause tiny leaks in brain blood vessels, prompting neutrophils to respond and prevent further damage. Over time, these cells could become more rigid and trapped in the brain, causing additional inflammation.

Dr. Mary-Ellen Lynall noted that there has long been an understanding that neutrophils behave differently after stressful events, but until now, the exact implications for mood and behavior were not fully understood. Their work demonstrates that these immune cells migrate from the skull to the brain where they can directly affect mood.

Many people experience temporary mood changes due to immune response, like when feeling unwell with a cold. If the immune system remains in a pro-inflammatory state, it’s not surprising that long-term mood issues may occur.

The study results could serve as a potential biomarker for identifying mood disorders linked to inflammation, assisting in the search for more effective treatments. For instance, a clinical trial targeting brain inflammation in depression might fail if conducted on a general population. However, using specific biomarkers could help focus on those whose depression is related to inflammation, thereby increasing the trial’s success rate.

Additionally, these findings could provide insights into why depression often appears in other neurological disorders, further complicating conditions such as stroke and Alzheimer’s. It raises the question of whether neutrophils responding to brain damage could trigger mood disorders, or if depression itself might heighten the risk of such neurological diseases later in life.

This research was funded by multiple health organizations, including the National Institute of Mental Health and the Medical Research Council.