Abstract
The inflammatory hypothesis of depression is one of the main theories that endeavors to explain and describe the underlying biological mechanisms of depression and suicide. While mounting evidence indicates altered peripheral and central inflammatory profiles in depressed patients and suicide completers, little is known about how peripheral and central inflammation might be linked in these contexts. The choroid plexus (ChP), a highly vascularized tissue that produces cerebrospinal fluid (CSF) and lacks a blood–brain–barrier, is an interface between peripheral and central immune responses. In the present study, we investigated the cellular and molecular inflammatory profile of the ChP of the lateral ventricle in depressed suicides and psychiatrically healthy controls. Gene expression of macrophages, pro- and anti-inflammatory cytokines, and various factors implicated in immune cell trafficking were measured; and density of ionized calcium-binding adaptor molecule 1-positive (Iba1+) macrophages associated with the ChP epithelial cell layer (ECL) was examined. Significant downregulations of the genes encoding interleukin 1ß (IL1ß), a pro-inflammatory acute-phase protein; intercellular cell adhesion molecule 1 (ICAM1), a protein implicated in immune cell trafficking in the ChP; and IBA1, a monocyte/macrophage marker; were detected in depressed suicides as compared to controls. No difference in the density of Iba1+ macrophages associated with the ChP ECL was observed. While interpretation of these findings is challenging in the absence of corroborating data from the CSF, peripheral blood, or brain parenchyma of the present cohort, we hypothesize that the present findings reflect a ChP compensatory mechanism that attenuates the detrimental effects of chronically altered pro-inflammatory signaling caused by elevated levels of pro-inflammatory cytokines, such as IL-1ß, peripherally and/or centrally. Together, these findings further implicate neuroimmune processes in the etiology of depression and suicide.
Highlights
Depression affects over 350 million people globally and is the leading cause of disability worldwide [1]
intercellular cell adhesion molecule 1 (ICAM1) gene expression was significantly downregulated in depressed suicides (DS) compared to CTRL subjects (t(20) = 3.647, p = 0.002) (Figure 3A), but there were no significant differences in VCAM1 or MCP1 transcript expression between groups (Figures 3B,C)
Three-group comparisons were performed to assess the potential effects of antidepressant treatment (ADT) on the expression of the investigated genes, as ADT has been reported to modulate expression levels of peripheral pro-inflammatory cytokines in depressed patients [(41, 42); for a review, see Ref. [43]]
Summary
Depression affects over 350 million people globally and is the leading cause of disability worldwide [1]. Studies have consistently implicated mood disorders, including major depressive disorder (MDD), as a common factor underlying suicide. 50% of children, adolescents, and adults who die by suicide have a prior mood disorder diagnosis, most commonly MDD [2, 3]. As many as 15% of individuals with a lifetime diagnosis of MDD admit to having attempted suicide at least once during their lives [4]. As the relative contribution of depression to the global burden of disease increases, it becomes increasing important to understand its biological underpinnings, as well as those of suicide, a global leading cause of death that claims the lives of more than 800,000 people annually [5]. The inflammatory hypothesis of depression is one of the main theories that endeavors to explain and describe the underlying biological mechanisms of depression and suicide outcomes. Maes et al [9] later expanded this theory in the form of the “Monocyte-T-Lymphocyte Hypothesis of Depression.” A substantial number of studies have been undertaken to investigate the various aspects of this hypothesis, and a large literature has emerged in support of it
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