Chronic stress has far-reaching effects on our bodies. Many stress-related psychiatric diseases, including depression, are linked to immune system abnormalities. However, the basic mechanisms governing how these alterations influence the brain remain largely unclear.
An international research team, led by the University of Zurich (UZH), the University Hospital of Psychiatry Zurich (PUK), and the Icahn School of Medicine at Mount Sinai, New York, has discovered a new mechanism. The team found that stress increases the levels of matrix metalloproteinase-8 (MMP-8), an enzyme in the blood of mice, and similar changes were observed in patients with depression. MMP-8 moves from the blood to the brain, where it affects the functioning of specific neurons. In the mice, this results in behavioral changes, causing them to withdraw and avoid social interaction, as explained by first author Flurin Cathomas.
Cathomas states that the discoveries are unique in two ways: Firstly, they suggest a new connection between the body and mind, which could have implications not only for mental illnesses related to stress, but also for other conditions affecting both the immune and nervous systems. Additionally, the identification of the MMP-8 protein could serve as a promising foundation for the development of new depression treatments, according to the psychiatrist.
The researchers were able to use animal models to show that stress increases the migration of a specific type of white blood cells called monocytes into the vascular system of the brain, particularly into the reward center regions. These monocytes produce MMP-8. MMP-8 is involved in the restructuring and regulation of the net-like frame that surrounds neurons in the brain - called the extracellular matrix. "If MMP-8 penetrates the brain tissue from the blood, it changes the matrix structure and thus disrupts the functioning of the neurons. Mice who are affected by this process display changes in behavior that are similar to those seen in humans with depression," says Flurin Cathomas.
To demonstrate MMP-8's role in behavioral changes, scientists deleted the MMP-8 gene from certain mice. These mice did not exhibit stress-related negative behaviors, unlike the control group. The study suggests that the findings in mouse models may be applicable to humans with depression, as both monocytes and MMP-8 were elevated in the blood of depressed individuals compared to healthy subjects.
More research is required before the findings can be used in clinical practice. However, Cathomas emphasizes that their work highlights the significance of the relationship between the immune system and the brain in the emergence of psychiatric conditions. These findings are already influencing psychiatric treatment, particularly on the PUK's specialized ward for integrative care overseen by Cathomas, where clinicians adopt a comprehensive approach based on the most recent scientific discoveries when caring for their patients.
The research team is currently preparing to conduct clinical trials to examine how stimulating specific areas of the brain can affect the immune system. Additionally, they will assess whether alterations in the immune system cells of individuals with depression impact their behavior.