Stress Influences Brain and Psyche via Immune System

UZH researchers now show that a particular enzyme found in cells of the immune system enters the brain under stress. In mice, it causes them to withdraw and avoid social contact. This newly discovered connection between body and mind in stress-related mental illnesses could lead to new treatments for depression.

An international research team 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.

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.

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.

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.

Sources:

Flurin Cathomas, Hsiao-Yun Lin, Kenny L. Chan, Long Li, Lyonna F. Parise, Johana Alvarez, Romain Durand-de Cuttoli, Antonio V. Aubry, Samer Muhareb, Fiona Desland, Yusuke Shimo, Aarthi Ramakrishnan, Molly Estill, Carmen Ferrer-Pérez, Eric M. Parise, C. Matthias Wilk, Manuella P. Kaster, Jun Wang, Allison Sowa, William G. Janssen, Sara Costi, Adeeb Rahman, Nicolas Fernandez, Matthew Campbell, Filip K. Swirski, Eric J. Nestler, Li Shen, Miriam Merad, James W. Murrough, Scott J. Russo. Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature, 2024; DOI: 10.1038/s41586-023-07015-2

University of Zurich. “Stress influences brain and psyche via immune system.” ScienceDaily. ScienceDaily, 7 February 2024. <www.sciencedaily.com/releases/2024/02/240207120515.htm>.

Materials provided by University of Zurich. Note: Content may be edited for style and length.

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