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 proteinase specific to myeloid cells.
In the serum of humans with major depressive disorder (MDD) and of 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 the neurophysiology of the nucleus accumbens (a key part of the brain’s reward circuitry, involved in pleasure, reinforcement learning, and processing). of motivation and reward), as well as altered social behavior.
Depletion of this MMP in these mice stopped social avoidance behavior caused by stress and halted changes in the neurophysiology of the nucleus accumbens and ECM. This mechanism, by which peripheral immune factors can affect the function and behavior of the central nervous system in the context of stress, could constitute new therapeutic targets for stress-related neuropsychiatric disorders.
The research article, “Circulating myeloid-derived MMP8 in susceptibility to stress and depression,“was published in Nature.
The body keeps score
Psychosocial stress profoundly affects the body, including the immune system and brain. Several studies have shown or suggested that behavioral changes are caused by peripheral immune factors such as cytokines or different cell types. These studies have demonstrated 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 alterations in the peripheral immune system to stress-related disorders such as MDD, the underlying mechanisms are not well understood.
Circulating MMPs 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 peripheral immune system MMPs affect psychosocial stress.
Flurin Cathomas, PhD, and colleagues showed a unique way that stress affects the brain and how it controls social behavior. Immune cells secrete MMPs into the bloodstream, which changes the ECM and ultimately brain function. The researchers demonstrated that the expression of a proteinase specific to circulating myeloid cells, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD, as well as in stress-susceptible mice after chronic social defeat stress ( CSDS).
In mice, this increase leads to alterations in the extracellular space, neurophysiological changes in the nucleus accumbens, and altered social behavior. In stress-susceptible mice, circulating monocytes and monocytes traveling to the brain showed increased Mmp8 expression after chronic social stress. Circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. MMP8 depletion prevented stress-induced social avoidance behavior and alterations in NAc neurophysiology and extracellular space.
Together, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress. Targeting matrix metalloproteinases derived from specific peripheral immune cells could constitute new therapeutic targets for stress-related neuropsychiatric disorders. These results provide us with important insights into the increasing role of neuroimmune mechanisms in neuropsychiatric disorders and provide new peripheral targets for advanced biomarkers and treatment options. One question that needs to be addressed in future studies is the extent to which region-specific monocyte trafficking allows local delivery of secreted factors such as MMP8. More research is needed to unravel the neuroimmune mechanisms of stress-induced alterations in social and non-social behavior.