New therapeutic targets for stress related disorders

Scientists at the Mount Sinai School of Medicine have discovered a novel mechanism by which the immune system affects central nervous system (CNS) function and behaviour, which could lead to new therapeutic targets for stress related disorders.

During stress, monocytes, derived in the bone marrow and released into the bloodstream, are drawn into sites in the brain that control emotional behaviours. There, they release an enzyme named matrix metalloproteinase 8 (MMP8) that breaks down proteins and restructures the brain to change neuron function.

Lead author Dr Flurin Cathomas, Instructor of Neuroscience and member of the Brain-Body Research Center at Mount Sinai, commented: “Psychosocial stress is a major factor for developing major depressive disorder and post-traumatic stress disorder (PTSD) and has been shown to have profound effects on the body, including the immune system and the brain.”

He continued: “These data are the first to show that immune cells derived in the bone marrow – and not the brain – can be recruited during stressful circumstances to the brain, setting off a cascade of other mechanisms that alter brain function and behaviour.”

The research team conducted a comparative cross-species analyses in mice and humans to explore these mechanisms and discovered that MMP8 is elevated in the serum of study subjects with major depressive disorder, and in stress-susceptible mice following chronic social defeat stress, which is a model of social trauma. The studies in mice established that peripheral MMP8 enters the brain through damaged blood vessels to restructure the brain’s extracellular tissue matrix, which results in altered function of neurons that ultimately impairs social behaviour and reward.

Most hypotheses about the role of the immune system in stress disorders prior to this work have focused on mechanisms related to microglia, and their ability to release pro-inflammatory molecules like interleukins to control neural function and behaviour. Single-cell RNA sequencing was used to examine the gene expression profiles in circulating monocytes compared to microglia. However, contrary to popular belief, the microglia did not exhibit a pro-inflammatory gene signature and the team had no evidence that they upregulate genes that code for interleukins. This contrasted with circulating monocytes found within the blood vessel lining of brain regions that control mood and emotion.

“There are no existing medications to target MMP8, and while it’s not yet clear if such treatments will ultimately be effective in treating depression, my hope is that this study will lead to renewed effort in developing such drugs,” elucidated Dr Scott Russo, Mount Sinai Professor in Affective Neuroscience, Leon Levy Director of the Brain-Body Research Center, and Center for Affective Neuroscience at Mount Sinai. “It’s also possible that non-pharmacological ‘lifestyle’ strategies to promote positive immune health might be helpful in treating these stress-related disorders.”

As the disturbances in the immune system were only found in a subset of patients, this showed the heterogenous nature of stress-related disorders. The studies performed in human subjects were correlative, so the team did not establish if treatments targeting monocytes or MMP8 directly will be effective for human stress disorders. Notably, there are multiple additional MMPs that can be derived directly in the brain and it is unclear whether they play complementary or opposing roles.

Dr Russo added: “The brain and the body are unequivocally connected and we are really at the precipice of a markedly deeper understanding of how the connections between the brain and peripheral organ systems like the immune system, cardiovascular system, and others can affect a person’s health.”

He concluded: “Our work suggests that strategies to promote immune health can benefit one’s emotional well-being and possibly prevent stress-related illnesses like depression and PTSD. Additional research for continued understanding and potential treatment development is warranted.”

At present, the team are testing therapeutic strategies to inhibit MMP8 as novel antidepressants and are exploring MMP8 as an immune biomarker for depression patients.

This study was published in Nature.