According to new research from the Icahn School of Medicine at Mount Sinai, stress promotes immune cell interactions with the brain to control social behavior through a circulating myeloid cell-specific proteinase.

In the serum of humans with major depressive disorder (MDD) and stress-susceptible mice subjected to chronic stress, the researchers identified increases in a specific matrix metalloproteinase (MMP). In these mice, increases in this MMP lead to alterations in the extracellular matrix (ECM) and neurophysiology of the nucleus accumbens—a key part of the brain’s reward circuit, which is involved in pleasure, reinforcement learning, and processing motivation and reward—as well as altered social behavior.

Depleting this MMP in these mice stopped the social avoidance behavior caused by stress and stopped changes in the nucleus accumbens neurophysiology and ECM. This mechanism, by which peripheral immune factors can affect central nervous system function and behavior in the context of stress, could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

The research article, “Circulating myeloid-derived MMP8 in stress susceptibility and depression,” was published in Nature.

The body takes the score

Psychosocial stress profoundly affects the body, including the immune system and the brain. A number of studies have shown or suggested that changes in behavior are caused by peripheral immune factors like cytokines or different types of cells. These studies have shown or suggested mechanisms that directly affect neurons, such as the binding of cytokines to receptors found on neurons. Although a large number of preclinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as MDD, the underlying mechanisms are not well understood.

MMPs in circulation have been associated with numerous inflammatory processes and disorders, such as cancer and myocardial infarction. Several studies have shown that MMPs in the central nervous system change parts of the ECM to affect synaptic remodeling and transmission. However, little is known about how MMPs from the peripheral immune system affect psychosocial stress.

Flurin Cathomas, PhD, and his colleagues showed a unique way that stress affects the brain and how it controls social behavior. The immune cells secrete MMPs into the bloodstream, changing the ECM and, ultimately, brain function. The researchers showed that the 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, this increase leads to alterations in extracellular space, neurophysiological changes in the nucleus accumbens, and altered social behavior. In stress-susceptible mice, circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. Circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting 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 affect central nervous system function and behavior in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders. These results give us important information about the growing role of neuroimmune mechanisms in neuropsychiatric disorders and provide new peripheral targets for advanced biomarkers and treatment options. A question that needs to be addressed in future studies is the extent to which region-specific monocyte trafficking enables local delivery of secreted factors such as MMP8. Further research is needed to disentangle the neuroimmune mechanisms of stress-induced social versus nonsocial behavioral alterations.

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