Stress significantly impacts the immune system and brain, contributing to stress-related disorders like major depressive disorder (MDD). This study shows that circulating myeloid-derived matrix metalloproteinase 8 (MMP8) is increased in the serum of humans with MDD and in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, elevated MMP8 levels lead to changes in the extracellular space and neurophysiological alterations in the nucleus accumbens (NAc), as well as altered social behavior. Using mass cytometry and single-cell RNA sequencing, the study found that peripheral monocytes are strongly affected by stress, with increased Mmp8 expression in both circulating monocytes and those that traffic to the brain. 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. These findings 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. Stress-related neuropsychiatric disorders such as MDD have a high worldwide prevalence and tremendous individual burden. Although there are many effective treatments for MDD, more than a third of affected individuals do not achieve full remission following treatment with available antidepressant medications or established psycho-therapeutic treatments. One of the most important risk factors for depression is chronic psychosocial stress. Therefore, elucidating the pathophysiological mechanisms underlying the effects of psychosocial stress is crucial to advancing our understanding of disorders such as MDD and ultimately developing treatment options and prevention strategies. Immune interactions between the central nervous system (CNS) and peripheral organ systems are tightly regulated. Psychosocial stress can affect this bidirectional communication profoundly, and disrupted neuroimmune interactions are increasingly recognized as important factors in the pathogenesis of stress disorders. Chronic stress activates the innate immune system, resulting in mobilization of peripheral myeloid cells (for example, monocytes and neutrophils) and the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6). In humans, it is well established that a subset of patients with stress-related neuropsychiatric disorders, such as MDD, display a state of chronic low-grade inflammation, characterized by increased circulating pro-inflammatory cytokines and leukocytosis. In addition to these peripheral immune changes, stress disrupts the endothelial blood–brain barrier (BBB) in mice, allowing greater entry of circulating proteins directly into brain reward regions. Although these findings have provided important insights into the pathophysiology of stress and depression, we still know relatively little about the mechanisms by which these stress-induced immune changes affect neuronal function and ultimately behaviour. In the brain, neurons and non-neuronalStress significantly impacts the immune system and brain, contributing to stress-related disorders like major depressive disorder (MDD). This study shows that circulating myeloid-derived matrix metalloproteinase 8 (MMP8) is increased in the serum of humans with MDD and in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, elevated MMP8 levels lead to changes in the extracellular space and neurophysiological alterations in the nucleus accumbens (NAc), as well as altered social behavior. Using mass cytometry and single-cell RNA sequencing, the study found that peripheral monocytes are strongly affected by stress, with increased Mmp8 expression in both circulating monocytes and those that traffic to the brain. 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. These findings 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. Stress-related neuropsychiatric disorders such as MDD have a high worldwide prevalence and tremendous individual burden. Although there are many effective treatments for MDD, more than a third of affected individuals do not achieve full remission following treatment with available antidepressant medications or established psycho-therapeutic treatments. One of the most important risk factors for depression is chronic psychosocial stress. Therefore, elucidating the pathophysiological mechanisms underlying the effects of psychosocial stress is crucial to advancing our understanding of disorders such as MDD and ultimately developing treatment options and prevention strategies. Immune interactions between the central nervous system (CNS) and peripheral organ systems are tightly regulated. Psychosocial stress can affect this bidirectional communication profoundly, and disrupted neuroimmune interactions are increasingly recognized as important factors in the pathogenesis of stress disorders. Chronic stress activates the innate immune system, resulting in mobilization of peripheral myeloid cells (for example, monocytes and neutrophils) and the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6). In humans, it is well established that a subset of patients with stress-related neuropsychiatric disorders, such as MDD, display a state of chronic low-grade inflammation, characterized by increased circulating pro-inflammatory cytokines and leukocytosis. In addition to these peripheral immune changes, stress disrupts the endothelial blood–brain barrier (BBB) in mice, allowing greater entry of circulating proteins directly into brain reward regions. Although these findings have provided important insights into the pathophysiology of stress and depression, we still know relatively little about the mechanisms by which these stress-induced immune changes affect neuronal function and ultimately behaviour. In the brain, neurons and non-neuronal