Decoding the Inflammatory Signature of the Major Depressive Episode: Insights from Peripheral Immunophenotyping in Active and Remitted Condition

Abstract

Although the immune system's role in the pathogenesis and persistence of depression is increasingly recognized, there is a lack of comprehensive understanding regarding the involvement of innate and adaptive immune cells. This study aims to bridge this knowledge gap by providing a deepening assessment of immunological profiles integrated into clinical and biochemical parameters in individuals with Major Depressive Episode (MDE). This multicenter case-control sex and age-matched study recruiting 121 participants divided into patients with active and remitted MDE and healthy controls (HC). Biochemical parameters, humoral responses (pro- and anti-inflammatory), and specific innate and adaptive immune cell populations were measured. Patients with MDE showed monocytosis, increased high-sensitivity C-reactive protein and Erythrocyte Sedimentation Rate levels, and an altered proportion of specific monocyte subsets. CD4 lymphocytes exhibited increased activation and exhaustion and a higher frequency of CD4+CD25+FOXP3+ regulatory T cells. Additionally, patients with MDE showed increased plasma levels of sTREM2, IL-17 and IL-6. This profile denoted an immune dysregulation and inflammation in MDE. Boruta analyses identified markers with significant discriminative potential for distinguishing between patients with MDE and HC. Cluster analysis revealed that patients with MDE exhibited at least three different patterns of immune system activation, suggesting a different stage of inflammation or possible differences in the underlying mechanism involved. Our findings give a deeper understanding of the role of inflammation and its mediators in MDE, illuminating the way for novel therapeutic strategies tailored to specific subgroups of patients.