Immune cells released from bone marrow in the skull in response to chronic stress and adversity could play a key role in symptoms of depression and anxiety, say researchers.
There's a significant proportion of people for whom antidepressants don't work. If we can figure out what's happening with the immune system, we may be able to alleviate or reduce depressive symptoms
Stacey Kigar
The discovery - found in a study in mice - sheds light on the role that inflammation can play in mood disorders and could help in the search for new treatments, in particular for those individuals for whom current treatments are ineffective.
Around 1 billion people will be diagnosed with a mood disorder such as depression or anxiety at some point in their life. While there may be many underlying causes, chronic inflammation - when the body's immune system stays active for a long time, even when there is no infection or injury to fight - has been linked to depression. This suggests that the immune system may play an important role in the development of mood disorders.
Previous studies have highlighted how high levels of an immune cell known as a neutrophil, a type of white blood cell, are linked to the severity of depression. But how neutrophils contribute to symptoms of depression is currently unclear.
In research published today in Nature Communications, a team led by scientists at the University of Cambridge, UK, and the National Institute of Mental Health, USA, tested a hypothesis that chronic stress can lead to the release of neutrophils from bone marrow in the skull. These cells then collect in the meninges - membranes that cover and protect your brain and spinal cord - and contribute to symptoms of depression.
As it is not possible to test this hypothesis in humans, the team used mice exposed to chronic social stress. In this experiment, an 'intruder' mouse is introduced into the home cage of an aggressive resident mouse. The two have brief daily physical interactions and can otherwise see, smell, and hear each other.
The researchers found that prolonged exposure to this stressful environment led to a noticeable increase in levels of neutrophils in the meninges, and that this was linked to signs of depressive behaviour in the mice. Even after the stress ended, the neutrophils lasted longer in the meninges than they did in the blood. Analysis confirmed the researchers' hypothesis that the meningeal neutrophils - which appeared subtly different from those found in the blood - originated in the skull.
Further analysis suggested that long-term stress triggered a type of immune system 'alarm warning' known as type I interferon signalling in the neutrophils. Blocking this pathway - in effect, switching off the alarm - reduced the number of neutrophils in the meninges and improved behaviour in the depressed mice. This pathway has previously been linked to depression - type 1 interferons are used to treat patients with hepatitis C, for example, but a known side effect of the medication is that it can cause severe depression during treatment.
Dr Stacey Kigar from the Department of Medicine at the University of Cambridge said: "Our work helps explain how chronic stress can lead to lasting changes in the brain's immune environment, potentially contributing to depression. It also opens the door to possible new treatments that target the immune system rather than just brain chemistry.
"There's a significant proportion of people for whom antidepressants don't work, possibly as many as one in three patients. If we can figure out what's happening with the immune system, we may be able to alleviate or reduce depressive symptoms."
The reason why there are high levels of neutrophils in the meninges is unclear. One explanation could be that they are recruited by microglia, a type of immune cell unique to the brain. Another possible explanation is that chronic stress may cause microhaemorrhages, tiny leaks in brain blood vessels, and that neutrophils - the body's 'first responders' - arrive to fix the damage and prevent any further damage. These neutrophils then become more rigid, possibly getting stuck in brain capillaries and causing further inflammation in the brain.
Dr Mary-Ellen Lynall from the Department of Psychiatry at the University of Cambridge said: "We've long known that something is different about how neutrophils behave after stressful events, or during depression, but we didn't know what these neutrophils were doing, where they were going, or how they might be affecting the brain and mind. Our findings show that these 'first responder' immune cells leave the skull bone marrow and travel to the brain, where they can influence mood and behaviour.
"Most people will have experienced how our immune systems can drive short-lived depression-like symptoms. When we are sick, for example with a cold or flu, we often lack energy and appetite, sleep more and withdraw from social contact. 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."
The findings could provide a useful signature, or 'biomarker', to help identify those patients whose mood disorders are related to inflammation. This could help in the search for better treatments. For example, a clinical trial of a potential new drug that targets inflammation of the brain in depression might appear to fail if trialled on a general cohort of people with depression, whereas using the biomarker to identify individuals whose depression is linked to inflammation could increase the likelihood of the trial succeeding.
The findings may also help explain why depression is a symptom common in other neurological disorders such as stroke and Alzheimer's disease, as it may be the case that neutrophils are being released in response to the damage to the brain seen in these conditions. But it may also explain why depression is itself a risk factor for dementia in later life, if neutrophils can themselves trigger damage to brain cells.
The research was funded by the National Institute of Mental Health, Medical Research Council and National Institute for Health and Care Research Cambridge Biomedical Research Centre.
Reference
Kigar, SL et al. Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice. Nat Comms; 1 Sept 2025; DOI: 10.1038/s41467-025-62840-5
