This study investigates the role of circulating myeloid-derived matrix metalloproteinase 8 (MMP8) in stress susceptibility and depression. The authors found that MMP8 levels are increased in the serum of individuals with major depressive disorder (MDD) and in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, this increase leads to alterations in the extracellular space (ECS) and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behavior. Using mass cytometry and single-cell RNA sequencing, they demonstrate that peripheral monocytes are significantly affected by stress, with both circulating monocytes and those that traffic to the brain showing increased MMP8 expression after CSDS. MMP8 directly infiltrates the NAc parenchyma and controls the ECS. Depleting MMP8 prevents stress-induced social avoidance behavior and alterations in NAc neurophysiology and ECS. These findings establish a mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress, suggesting that targeting specific peripheral immune cell-derived MMPs could be a novel therapeutic approach for stress-related neuropsychiatric disorders.This study investigates the role of circulating myeloid-derived matrix metalloproteinase 8 (MMP8) in stress susceptibility and depression. The authors found that MMP8 levels are increased in the serum of individuals with major depressive disorder (MDD) and in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, this increase leads to alterations in the extracellular space (ECS) and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behavior. Using mass cytometry and single-cell RNA sequencing, they demonstrate that peripheral monocytes are significantly affected by stress, with both circulating monocytes and those that traffic to the brain showing increased MMP8 expression after CSDS. MMP8 directly infiltrates the NAc parenchyma and controls the ECS. Depleting MMP8 prevents stress-induced social avoidance behavior and alterations in NAc neurophysiology and ECS. These findings establish a mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress, suggesting that targeting specific peripheral immune cell-derived MMPs could be a novel therapeutic approach for stress-related neuropsychiatric disorders.