Summary: New research in mice shows that chronic stress can cause neutrophils—an immune cell type—to leave skull bone marrow and accumulate in the meninges, the membranes that protect the brain. These meningeal neutrophils are linked to depressive-like behaviors, and blocking a specific immune alarm pathway (type I interferon signaling) reduced neutrophil accumulation and improved mood-related behaviors in the study animals.
The study provides evidence of how prolonged stress reshapes the brain’s immune environment and suggests why many people with depression may not respond to conventional antidepressants. The immune changes could serve as biomarkers for inflammation-related mood disorders and point toward alternative, immune-targeted treatments. The findings also offer possible explanations for the overlap between depression and neurological disorders such as stroke and Alzheimer’s disease.
Key Facts
- Immune link: Chronic stress promotes movement of neutrophils from skull bone marrow into the meninges, where they can influence mood.
- Signaling pathway: Type I interferon signaling appears to drive meningeal neutrophil accumulation; blocking this pathway reduced both neutrophils and depressive behaviors in mice.
- Treatment implications: These results support developing immune-focused diagnostics and therapies for depression that is resistant to standard antidepressants.
Source: University of Cambridge
Immune cells released from skull bone marrow after prolonged stress may contribute to depression and anxiety, say researchers.
In a mouse model of chronic social stress, researchers observed a sustained influx of neutrophils into the meninges—tissues that envelop the brain and spinal cord. These immune cells were associated with behaviors commonly interpreted as depressive in rodents. The work sheds light on the role of chronic inflammation in mood disorders and highlights potential new avenues for treatment, especially for people who do not respond to current antidepressant medications.
Mood disorders are widespread—an estimated one billion people will face conditions such as depression or anxiety during their lifetime. While many biological and environmental factors contribute to these disorders, persistent inflammation has emerged as an important component that may affect symptoms and treatment response.
Previous clinical and experimental studies have associated elevated neutrophil counts with more severe depressive symptoms, but the mechanisms behind this association were unclear. The new study, published in Nature Communications, specifically tested whether chronic stress mobilizes neutrophils from skull bone marrow into the brain’s protective membranes, and whether those neutrophils influence behavior.
Because direct investigation in humans is not feasible, the team used a validated chronic social defeat (CSD) stress paradigm in male mice. In this model, an “intruder” mouse is repeatedly exposed to an aggressive resident, producing prolonged social stress through daily, short encounters and constant sensory exposure between interactions.
Mice exposed to CSD showed a clear increase in neutrophils within the meninges. Notably, these meningeal neutrophils persisted longer than elevated neutrophil levels in the bloodstream after the stress ended. Genetic and transcriptional analyses indicated that the meningeal neutrophils originated in the skull bone marrow and displayed a distinct molecular profile compared with blood neutrophils.
Further investigation identified enhanced type I interferon (IFN-I) signaling in meningeal neutrophils following chronic stress. Interferons are immune signaling molecules that act as an alarm system; prolonged activation can have wide-ranging effects. When researchers blocked the IFN-I receptor (IFNAR) in the mouse model, meningeal neutrophil counts declined and stress-related behavioral deficits were reduced, implicating IFN-I signaling as a mediator of this process.
Type I interferons have clinical relevance: for example, IFN-I treatments used in other medical contexts (such as hepatitis C therapy) are known to trigger depressive symptoms in some patients, reinforcing the link between this pathway and mood regulation.
The reasons neutrophils accumulate in the meninges remain to be fully clarified. The research team proposes several possibilities: meningeal microglia (specialized brain immune cells) might recruit neutrophils, or chronic stress could cause microhaemorrhages—tiny vascular leaks—prompting neutrophils to respond to vascular damage. Once in the meninges, neutrophils may become less deformable, potentially obstructing small vessels and amplifying local inflammation.
Dr Stacey Kigar from the Department of Medicine at the University of Cambridge commented that the work helps explain how prolonged stress can produce durable changes in the brain’s immune landscape and that targeting immune mechanisms may offer new options for people who do not benefit from standard antidepressants.
Dr Mary-Ellen Lynall from the Department of Psychiatry noted that while transient, sickness-related low mood is familiar to many, chronic pro-inflammatory states may underlie longer-lasting mood disturbances. Identifying an inflammatory signature could allow clinicians to stratify patients and test anti-inflammatory approaches in those most likely to benefit.
The study’s findings could also help explain why depression commonly occurs alongside neurological diseases such as stroke and Alzheimer’s disease: neutrophil recruitment to the meninges might be a response to brain injury in these conditions. Conversely, if neutrophils themselves contribute to neural damage, their chronic presence could increase dementia risk over time.
Funding: The research was supported by the National Institute of Mental Health, the Medical Research Council, and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.
About this neuroscience and depression research news
Author: Craig Brierley
Source: University of Cambridge
Contact: Craig Brierley – University of Cambridge
Image: The image is credited to Neuroscience News
Original Research: Open access. “Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice” by Stacey Kigar et al., Nature Communications. DOI: 10.1038/s41467-025-62840-5
Abstract
Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice
Inflammation is increasingly recognized as a risk factor for psychiatric disorders. Animal stress models frequently show blood neutrophilia, but how this relates to symptoms and behavior is not well defined. This study examined immune responses at brain border regions in male mice subjected to chronic social defeat (CSD) stress.
The researchers found that chronic, but not acute, stress leads to a selective accumulation of neutrophils in the meninges—termed meningeal neutrophilia—without comparable infiltration into the brain parenchyma. CSD promotes neutrophil trafficking through vascular channels connecting skull bone marrow to the meninges. Transcriptional profiling indicated increased type I interferon signaling within meningeal neutrophils, and blocking IFN-I receptor signaling protected against CSD-induced behavioral deficits.
Identifying IFN-I signaling as a mediator of meningeal neutrophil recruitment points to potential therapeutic targets and diagnostic approaches for stress-related psychiatric conditions.