Inflammatory and Innate Immune Markers of Neuroprogression in Depressed and Teenage Suicide Brain

Several studies suggest that major depressive disorder (MDD) and bipolar disorder (BPD) are neuroprogressive illnesses. Besides clinical features, neurobiological mechanisms have been suggested to contribute to the neuroprogression of mood disorders. Biological factors that have been shown to contribute significantly toward the neuroprogressive course of these disorders are inflammatory markers, such as cytokines. Cytokines have been extensively investigated, primarily in the serum of MDD and BPD patients, and these studies show cytokine abnormalities in both adolescent and adult patients with mood disorders. However, cytokine abnormalities in the brain may also contribute toward neuroprogression, but brain cytokines have not been adequately investigated. To examine the role of cytokines in neuroprogression, we have studied the markers of adaptive and innate immunity in postmortem brain obtained from teenage and adult suicide victims and gene expression of cytokines and their membrane-bound receptors in lymphocytes of MDD and BPD patients. Cytokines and Toll-like receptors (TLRs) were studied in 24 teenage suicide victims and 24 normal control (NC) subjects, and also in 22 adult depressed suicide victims and 20 adult NC subjects. We found that the protein and mRNA expression of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were significantly higher in the prefrontal cortex (PFC). We also found that the protein and mRNA expression of TLRs, which are major mediators of innate immunity, is increased in the PFC of adult depressed suicide victims and NC subjects. In patients, mRNA and protein expression of TNF-α, IL-1β, and IL-6 was significantly increased in both MDD and BPD patients. Similarly, mRNA expression of some specific membrane-bound receptors, such as IL1R1, TNFR1, IL1RA, were significantly increased in lymphocytes of MDD and BPD patients. These studies indicate the existence of abnormal cytokines and TLRs in the brain of teenage and adult suicide victims. Future studies, including both teenage and adult postmortem samples, will be needed to further clarify the role of cytokines and TLRs in neuroprogression.