Immune cell enzyme links stress to depression

Immune cell enzyme links stress to depression

summary: Researchers have identified a new “mind-body mechanism” linking chronic stress to depression. They discovered that stress increases the enzyme matrix metalloproteinase 8 (MMP-8) in the blood, which then affects neurons in the brain, leading to social withdrawal behaviors in mice, a symptom observed in depression.

The identification of this enzyme opens up potential avenues for new treatments for depression by targeting MMP-8. In addition, the study highlights the critical role of the immune system’s interaction with the brain in psychiatric disorders, paving the way for clinical studies focusing on integrative mind-body care.

Key facts:

  1. The MMP-8 enzyme, which increases due to stress, travels from the blood to the brain, affecting nerve cell function and leading to depression-like behaviors.
  2. Removing the MMP-8 gene in mice prevented stress-related behavioral changes, mirroring findings in human depressed patients with elevated levels of MMP-8.
  3. Upcoming clinical studies aim to explore how affecting the immune system through brain stimulation can influence depressive behaviors, reflecting a comprehensive treatment approach.

source: University of Zurich

Chronic stress has far-reaching consequences on our bodies. For example, many stress-related mental illnesses such as depression are linked to changes in the immune system.

However, the underlying mechanisms of how these changes affect the brain remain largely unknown.

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The researchers were able to use animal models to show that stress increases the migration of a certain type of white blood cell called monocytes into the brain’s vascular system, especially to areas of the reward center. Credit: Neuroscience News

The enzyme found in immune cells in the blood affects nerves in the brain

An international research team led by the University of Zurich (UZH), Psychiatric University Hospital Zurich (PUK) and the Icahn School of Medicine at Mount Sinai, New York, has uncovered a new mechanism. “We were able to show that stress increases the amount of matrix metalloproteinase 8 (MMP-8), an enzyme found in the blood of mice.

“The same changes have been found in patients with depression,” says first author Florin Kathoumas. MMP-8 travels from the blood to the brain, where it changes the functioning of some nerve cells. In infected mice, this leads to behavioral changes: they withdraw and avoid social contact.

The possibility of finding new treatments for depression

According to Kathoumas, the findings are new in two ways: First, they point to a new “mind-body mechanism,” which may be relevant not only to stress-related mental illness, but also to other diseases that affect both immunity and the immune system. The nervous system.” Second, the psychiatrist says, identifying the specific MMP-8 protein could be a potential starting point for developing new treatments for depression.

Changes in the extracellular matrix in the brain

The researchers were able to use animal models to show that stress increases the migration of a certain type of white blood cell called monocytes into the brain’s vascular system, especially to areas of the reward center. These monocytes produce MMP-8. MMP-8 is involved in restructuring and organizing the mesh-like framework that surrounds neurons in the brain – called the extracellular matrix.

“If MMP-8 penetrates brain tissue from the blood, it changes the structure of the matrix and thus disrupts the functioning of neurons. Mice affected by this process show behavioral changes similar to those seen in depressed humans,” says Florin Kathoumas.

In order to prove that MMP-8 was truly responsible for the behavioral changes, the researchers removed the MMP-8 gene from some of the mice. Compared to control mice, these animals did not show negative stress-related behavioral changes.

“Blood analyzes of patients with depression suggest that findings from mouse models are also relevant to humans: both monocytes and MMP-8 were increased in the blood of people with depression compared to healthy participants.”

Clinical studies with patients are planned

More studies are needed before the results can be implemented in clinical practice. However, Kathoumas says: “Our work once again demonstrates the importance of the interaction between the immune system and the brain in the development of psychiatric disorders.

“These ideas are already being incorporated into psychotherapy today.” In PUK’s special wing for integrated care led by Kathoumas, doctors follow a comprehensive mind-body approach based on the latest scientific findings when treating their patients.

The research team is now planning to conduct clinical studies to find out the extent to which the immune system can be affected by stimulating specific areas of the brain. They will also look at whether any changes in depressed patients’ immune system cells affect their behaviour.

About this psychology research news

author: Melanie Niffler
source: University of Zurich
communication: Melanie Niffler – University of Zurich
Image: Image credit to Neuroscience News

Original search: Open access.
“Peripheral immune-derived matrix metalloproteinases enhance susceptibility to stress and depression” by Florin Kathoumas et al. nature

a summary

Immune-derived matrix metalloproteinase enhances susceptibility to stress and depression

Psychosocial stress has profound effects on the body, including the immune system and brain. Although a large number of preclinical 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 myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with major depressive disorder (MDD) as well as in rats exposed to stress after chronic social defeat stress (CSDS).

In mice, researchers have shown that this increase leads to changes in the extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behavior.

Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in the circulation and in the brain, and demonstrated that peripheral monocytes are strongly affected by stress.

In stress-exposed mice, both circulating monocytes and monocytes migrating to the brain showed an increase Mmp8 Expression after chronic social defeat stress. We also show that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space.

Depletion of MMP8 prevented stress-induced social avoidance behavior and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can influence CNS function and behavior in the context of stress.

Targeting matrix metalloproteinases derived from peripheral immune cells could constitute new therapeutic targets for stress-related neuropsychiatric disorders.

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