Signatures in the Protein Content of Human and Murine Blood Serum Exosomes, in the Context of Major Depressive Disorder, Are Associated with Cytokine Activity

Major depressive disorder (MDD) is among the most common and disabling psychiatric disorders. MDD is multifactorial, influencing the central nervous, endocrine, and immune systems. Also, MDD impacts neurochemical and inflammatory pathways via shared signaling mechanisms, including metabolites, soluble factors, and extracellular vesicles (EVs, including exosomes). Here, we hypothesized that EVs from MDD patients or mice exposed to chronic unpredictable mild stress (CUMS) contain specific inflammatory signatures that may help explain the pathophysiology of that mental disorder. We included four groups: healthy female controls (n = 8), women with MDD (n = 12), healthy Balb/C female mice (n = 10), and Balb/C mice under CUMS (n = 10). We isolated and characterized exosome-enriched EVs from human and murine serum and analyzed their protein content using antibody arrays. We identified three protein sets with significant differences (p < 0.05): 36 human exosome proteins decreased in the MDD group; 18 murine exosome proteins decreased in the CUMS group; and 12 proteins showed differential expression between human and murine exosomes, mostly trending downward in the CUMS and MDD groups. We performed bioinformatic analysis to determine protein–protein interactions and gene ontology functions. We identified signaling pathways associated with MDD and chronic stress: chemokine, cytokine–cytokine receptor, JAK-STAT, pathways in cancer, Rap1, Ras, TNF signaling, and cytokine interactions. These findings highlight the importance of human and murine exosomes as critical sources for understanding depression’s molecular mechanisms.