Enzyme released by immune cells may play role in depression

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Mount Sinai researchers have shown for the first time that immune cells called monocytes, derived from the bone marrow and released into the bloodstream, can be drawn during times of stress to sites in the brain that regulate emotional behavior. There, they secrete an enzyme called matrix metalloproteinase 8 (MMP8) that breaks down proteins and rewires the brain to alter neuron function and, ultimately, impair social behavior and reward.

These data establish a novel mechanism by which the immune system can influence central nervous system function and behavior in the context of stress, potentially opening the door to novel therapeutic targets for stress-related disorders. The study appears in the February 7 issue the nature.

Psychological stress is a major factor in the development of major depressive disorder and post-traumatic stress disorder (PTSD) and has been shown to have profound effects on the body’s immune system and brain. These data are the first to show that bone marrow-derived immune cells-; And not the brain-; The brain can be recruited to stressful situations, which sets off a cascade of other processes that alter brain function and behavior.


Florin Cathomas, MD, lead author, instructor of neuroscience and member of the Brain-Body Research Center at Mount Sinai

To explore these mechanisms, the research team performed a comparative cross-species analysis between mice and humans and found that MMP8 was elevated in the serum of study subjects with major depressive disorder as well as in stress-sensitive mice after chronic social defeat stress. The social trauma model. Studies in mice have confirmed that peripheral MMP8 enters the brain through damaged blood vessels to remodel the brain’s extracellular matrix, leading to altered neuronal function that ultimately impairs social behavior and reward.

Prior to this work, most hypotheses about the role of the immune system in stress disorders such as depression focused on mechanisms related to the brain’s resident immune cells, called microglia, and their ability to release pro-inflammatory molecules such as interleukins to regulate nerves. function and behavior.

Using single-cell RNA sequencing to look at gene expression profiles in circulating monocytes compared to microglia, the team found that, contrary to popular belief, microglia did not display a pro-inflammatory gene signature. The team found no evidence that they upregulated the genes that code for interleukin. This is in stark contrast to circulating monocytes found in the lining of blood vessels in brain regions that regulate mood and emotion.

“There are no existing drugs targeting MMP8, and while it is still unclear whether such treatments will ultimately be effective in treating depression, my hope is that this research will lead to new efforts in the development of such drugs,” said Scott Russo, Ph.D., Mt. Sinai Professor of Affective Neuroscience, director of the Center for Brain-Body Research and Mount Sinai’s Center for Affective Neuroscience. “It is also possible that non-pharmacological ‘lifestyle’ strategies to promote positive immune health may be helpful in the treatment of these stress-related disorders.”

The immune system disturbances identified in this study were only found in a subset of patients, highlighting the heterogeneous nature of such illnesses in terms of etiology. In addition, the studies performed in human subjects were purely correlational, so the team does not yet know whether treatments targeting monocytes or MMP8 will be directly effective for stress disorders in humans. Importantly, there are several additional MMPs that can be obtained directly in the brain, and it is unclear whether they play complementary or antagonistic roles.

“The brain and body are inextricably linked and we’re really on the verge of a really deep understanding of how connections between the brain and peripheral organ systems, such as the immune system, cardiovascular system and others, can affect a person’s health,” said Dr. Rousseau. “Our work suggests that strategies to promote immune health may benefit one’s psychological well-being and possibly prevent stress-related illnesses such as depression and PTSD. Additional research is warranted to continue understanding and develop potential treatments.”

The Mount Sinai research team is currently testing therapeutic strategies to inhibit MMP8 as novel antidepressants. They are investigating MMP8 as a novel immune biomarker for depression patients.

Source:

Journal Reference:

Catomas, F., etc (2024). Circulating myeloid-derived MMP8 in stress sensitivity and depression. the nature. doi.org/10.1038/s41586-023-07015-2.



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