Chronic stress leaves fingerprints in the brain’s protective covering. A new study from the University of Cambridge and the National Institute of Mental Health shows that immune cells released from skull bone marrow can accumulate in the meninges, triggering inflammation linked to depression-like behavior in mice.
The discovery, published in Nature Communications, points to type I interferon signaling as the key pathway and raises the possibility of new treatments for patients whose depression resists antidepressants.
Stress And The Brain’s Border
For decades, scientists have suspected that inflammation plays a role in mood disorders. Around one billion people worldwide will experience depression or anxiety, and up to a third will not respond to existing drugs. Previous work has shown that high levels of neutrophils, a white blood cell type, correlate with more severe depression, but their precise role remained elusive. The new study provides an answer: stress pushes neutrophils from the skull’s bone marrow into the meninges, where they linger, alter their signaling, and reshape mood.
“Our work helps explain how chronic stress can lead to lasting changes in the brain’s immune environment, potentially contributing to depression,” said Dr Stacey Kigar of the University of Cambridge.
A Model Of Social Defeat
The team turned to a well-established mouse paradigm known as chronic social defeat stress. In these experiments, an “intruder” mouse is exposed daily to a dominant aggressor. Over two weeks, the defeated mice not only developed anxiety- and depression-like behaviors but also showed a striking increase in meningeal neutrophils. These cells persisted for days after stress ended, long after blood levels had normalized, and they carried signatures of type I interferon activation. Blocking this pathway, in effect silencing the immune “alarm,” reduced neutrophil buildup and improved behavior in stressed mice.
The First Responders Stay Too Long
Why would neutrophils gather at the brain’s borders in the first place? One theory is that they are recruited by microglia, the brain’s resident immune cells. Another is that stress damages fragile blood vessels, leading to tiny leaks that call in neutrophils to repair the injury. In either case, the cells appear to become rigid and stall in capillaries, prolonging local inflammation. These findings may also help explain why depression is so common after stroke or in Alzheimer’s disease, conditions marked by brain injury and inflammation.
“Most people will have experienced how our immune systems can drive short-lived depression-like symptoms. If the immune system is always in a heightened, pro-inflammatory state, it shouldn’t be too surprising if we experience longer-term problems with our mood,” said Dr Mary-Ellen Lynall, Department of Psychiatry, University of Cambridge.
From Biomarker To Treatment
The implications extend beyond basic biology. If meningeal neutrophils leave a measurable signature, they could serve as a biomarker to identify patients whose depression is tied to inflammation. Clinical trials of anti-inflammatory drugs might then show clearer benefit when targeted to the right subgroup. And since interferon therapies are known to induce depression as a side effect, this study provides a mechanistic bridge between immune activation and mood.
The work underscores a growing theme in neuropsychiatry: that the immune system and the brain are entwined more tightly than once imagined. Depression, in this view, may not just be a chemical imbalance but also an inflammatory state sustained at the brain’s margins.
Explainer: What Are Meningeal Neutrophils?
The meninges are thin protective membranes that envelop the brain and spinal cord. Neutrophils, a type of white blood cell, are usually first responders to infection or injury. In the Cambridge–NIMH study, stress caused neutrophils from the skull bone marrow to migrate into the meninges. There, they became more inflammatory, activating type I interferon signaling. This immune alarm system, normally useful against viruses, instead appeared to worsen mood-related behaviors. By blocking interferon receptors, researchers reduced neutrophil accumulation and eased depressive symptoms in mice.
Journal: Nature Communications
DOI: 10.1038/s41467-025-62840-5
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