In a recent study published in Nature, researchers report a mechanism wherein peripheral immune factors could impact central nervous system (CNS) function and behavior under stress.
Study: Circulating myeloid-derived MMP8 in stress susceptibility and depression. Image Credit: SpeedKingz/Shutterstock.com
Background
Stress-related disorders such as major depressive disorder (MDD) have a high global prevalence. Although several effective treatments are available for MDD, more than one-third of affected people do not attain complete remission with current antidepressants or other psychotherapeutic treatments. Chronic psychosocial stress is a significant risk factor for depression.
Thus, exploring the mechanisms underlying the effects of psychosocial stress can help advance the understanding of MDD and develop prevention and treatment strategies. Immune interactions between peripheral organ systems and the CNS are tightly regulated, and psychosocial stress could profoundly impact this communication.
The study and findings
In the present study, researchers examined the effects and mechanisms of psychosocial stress on the immune system. They used the chronic social defeat stress (CSDS) paradigm, a validated mouse model of psychosocial stress, wherein an aggressive mouse subordinates the experimental mice through sensory exposure and physical contact.
The team phenotyped immune cells from unstressed control (CON), stress-susceptible (SUS), and resilient (RES) mice. CSDS decreased B cells and increased inflammatory monocytes and neutrophils in RES and SUS mice. Further, assessing leucocyte subpopulations in MDD patients revealed leukocytosis through increased neutrophils and monocytes relative to healthy controls.
The researchers observed that the number of circulating neutrophils and monocytes was positively correlated with perceived stress. Next, they examined leucocytes in the brains of mice without meninges after CSDS. They observed a specific increase in inflammatory monocytes in SUS mice only relative to CON mice. There were no differences in other leucocytes and brain-resident immune cells.
Increased monocytes in the leptomeninges were evident only in SUS mice. In the dura, monocyte increases were noted in RES and SUS mice. Monocyte frequency was unchanged in the choroid plexus. RNA sequencing revealed a pro-inflammatory transcriptional signature in SUS mice. Next, the team investigated where monocytes trafficked in the brain.
To this end, they performed anatomic mapping of monocytes. Consistently, increased monocytes were confirmed in SUS mice only. Cell counts in limbic brain regions, including the nucleus accumbens (NAc), were highly correlated with social interaction (SI) ratio. Increased numbers of monocytes in NAc correlated with increased social avoidance behavior.
Conversely, elevated monocyte trafficking was not observed in the prefrontal cortex (PFC). Next, single-cell RNA sequencing was performed on brain-trafficking monocytes following CSDS to examine their role in social avoidance. Unsupervised clustering revealed four clusters by transcriptional profiles. Several genes associated with inflammatory processes were upregulated in one of the clusters (cluster 0) enriched in SUS mice relative to RES and CON mice.
Gene ontology (GO) term analysis of upregulated cluster 0 genes revealed involvement in extracellular matrix (ECM), extracellular space (ECS), and oxidation-reduction processes. Matrix metalloproteinase 8 (Mmp8) was among the top genes enriched in ECM and ECS pathways and was also among the most differentially expressed genes in circulating monocytes in SUS mice.
Increased Mmp8 expression was not detected in monocytes from the dura, choroid plexus, and leptomeninges in SUS mice, indicating that circulating monocytes could be the probable MMP8 source in the brain. Additionally, stress-induced increases in MMP8 protein levels were confirmed in plasma post-CSDS. MMP8 levels showed a negative correlation with the SI ratio.
While plasma levels of MMP3 were higher, changes in SUS and RES mice were similar to CON mice, suggesting that MMP8 was uniquely upregulated in SUS mice only. Besides, increased serum MMP8 levels were noted in MDD patients relative to healthy controls, which positively correlated with perceived stress. MMP8 was elevated in the NAc of SUS mice but not the PFC.
The team generated chimeric mice with selective depletion of Mmp8, specifically in peripheral leucocytes. These mice showed less social avoidance following CSDS. Moreover, depletion did not affect other non-social stress-related behaviors. Mmp8-depleted mice showed reduced ECS of NAc. Mmp8 depletion also attenuated stress-induced neuronal excitability.
Conclusions
The findings revealed a distinct mechanism wherein stress promotes peripheral immune cell interactions with the brain and regulates social behavior. Additional investigations are required to identify other factors affecting ECS homeostasis. Taken together, the results offer insights into the role of neuroimmune mechanisms in neuropsychiatric disorders, highlighting that myeloid-derived MMPs could be novel therapeutic targets for stress-related disorders.
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