Summary: Researchers identified a novel ‘body-mind mechanism’ that links chronic stress to depression. They discovered that stress increases the enzyme matrix metalloproteinase-8 (MMP-8) in blood, which then impacts brain neurons, leading to social withdrawal behaviors in mice—a symptom observed in depression.
This enzyme’s identification opens up potential avenues for new depression treatments by targeting MMP-8. Additionally, the study highlights the critical role of the immune system’s interaction with the brain in psychiatric disorders, setting the stage for clinical studies focused on mind-body integrative care.
The enzyme MMP-8, increased by stress, crosses from the blood to the brain, affecting neuron function and leading to depression-like behaviors.
Removing the MMP-8 gene in mice prevented stress-related behavioral changes, mirroring findings in human depression patients with elevated MMP-8 levels.
Upcoming clinical studies aim to explore how influencing the immune system through brain stimulation can impact depressive behaviors, reflecting a holistic treatment approach.
Source: University of Zurich
Chronic stress has far-reaching consequences for our bodies. For example, many stress-related psychiatric illnesses such as depression are associated with changes in the immune system.
However, the underlying mechanisms of how these changes affect the brain are still largely unknown.
Enzyme from immune cells in the blood affects nerves in the brain
An international research team led by the University of Zurich (UZH), and the University Hospital of Psychiatry Zurich (PUK) and the Icahn School of Medicine at Mount Sinai, New York, has now uncovered a novel mechanism. “We were able to show that stress increases the amount of the matrix metalloproteinase-8 (MMP-8), an enzyme in the blood of mice.
The same changes were found in patients with depression,” says first author Flurin Cathomas. MMP-8 travels from the blood to the brain, where it alters the functioning of certain neurons. In the affected mice, this leads to behavioral changes: they withdraw and avoid social contact.
Potential for new treatments for depression
According to Cathomas, the findings are novel in two respects: “Firstly, they indicate a new ‘body-mind mechanism’, which might be relevant not only for stress-related mental illness, but also for other diseases that affect both the immune and nervous systems.” And secondly, says the psychiatrist, identification of the specific MMP-8 protein could be a potential starting point to develop new treatments for depression.
Changes to brain extracellular matrix
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.
In order to prove that MMP-8 was really responsible for the behavioral changes, the researchers removed the MMP-8 gene from some of the mice. Compared to the control mice, these animals did not display stress-related negative behavioral changes.
“Blood analyses of patients with depression indicate that the findings from the mouse models are also relevant for humans: both the monocytes and MMP-8 were increased in the blood of people with depression in comparison to healthy participants.”
Clinical studies with patients planned
Many more studies are needed before the results can be implemented in clinical practice. Nevertheless, says Cathomas, “our work once again demonstrates the importance of the interaction between the immune system and the brain in the development of psychiatric disorders.
“These insights are already being incorporated into psychiatric treatment today.” On the PUK’s special ward for integrative care led by Cathomas, the clinicians take a holistic mind-body approach based on the latest scientific findings when treating their patients.
The research team is now planning clinical studies to investigate the extent to which the immune system can be influenced by stimulating certain areas of the brain. They will also look at whether any changes in the immune system cells of depressive patients influence their behavior.
Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility and depression
Psychosocial stress has profound effects on the body, including the immune system and the brain. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD), the underlying mechanisms are not well understood.
Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS).
In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour.
Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress.
In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space.
Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress.
Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.