Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects

Abstract

The data in this study provide mechanistic insights into the dysregulation of the TNF-α gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.

A Specific Inflammatory Profile Underlying Suicide Risk? Systematic Review of the Main Literature Findings

“…The GR inducible target gene glucocorticoid-induced leucine zipper (GILZ) mRNA levels were decreased in PFC and amygdaloidal nuclei of these subjects as well. Based on another recent study [27], TNF-α expression was significantly higher in the dorsolateral prefrontal cortex (dlPFC) of suicide subjects regardless of psychiatric diagnosis, although its expression was enhanced even in major depressive disorder (MDD) subjects who died by causes other than suicide. Moreover, in a two-year follow-up study, Bay-Richter et al [28] demonstrated that quinolinic acid (QA) was increased and kynurenic acid (KYN) decreased in suicidal patients vs. healthy controls.…”

“…However, based on the selected studies and in line with a previously published paper of our research group upon the same topic [7], the existence of an association between inflammatory cytokines abnormalities and suicidal behavior does not necessarily reflect a specific causal link. Among the selected studies, eleven reports [8,9,12,[25][26][27][28][29][30][31][32] analyzed inflammatory cytokines abnormalities in suicidal patients, four [33][34][35][36] explored cytokines abnormalities in patients with both a positive history of suicide attempts and suicidal ideation, two [37,38] investigated the existence of inflammatory cytokines abnormalities levels in depressed patients with suicidal ideation vs. those abnormally without, seven [31,[40][41][42][43][44]50] examined the inflammatory cytokines abnormalities in patients with a history of suicide attempts vs. those without, three [45][46][47] analyzed patients died by suicide vs. those died for other causes, and two [48,49] focused on depressed suicidal patients with suicidality.…”

“…According to our findings, the most consistent link between inflammatory changes and suicidal behavior may be found in studies directly analyzing cytokines abnormalities and suicidal patients (completed suicides or those with a history of suicide attempts) when compared to healthy controls. Most of these studies documented abnormally higher levels of IL-1β, IL-6, TNF-α, TGF-β1, VEGF, and KYN, and lower levels of IL-2, IL-4, and IFN-γ predominantly in specific brain regions such as OFC, right ACC, insula, and dlPFC of suicidal patients (mainly suicide attempters) [8,9,12,[25][26][27][28][29][30][31][32]39,42,43]. Abnormally elevated IL-6 and IL-10 levels have also been reported in patients with active suicidal ideation when compared to healthy controls [37].…”

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

“…37 Furthermore, TNF mRNA levels in the frontopolar prefrontal cortex have also been reported in both non-suicide and suicide-completed individuals with major depression, and in suicide completers with other psychiatric diagnoses. 38 It is important to note, however, that these studies do not distinguish between soluble TNF and transmembrane TNF protein. Contrasting these findings, TNF mRNA levels have been reported to be unchanged in the dorsolateral prefrontal cortex and the anterior cingulate cortex from individuals with mood disorders when compared against non-psychiatric controls.…”

“…For instance, TNF protein and mRNA levels were reported as elevated, compared with controls, in the frontopolar prefrontal cortex of suicide‐completed, adolescent individuals who were depressed . Furthermore, TNF mRNA levels in the frontopolar prefrontal cortex have also been reported in both non‐suicide and suicide‐completed individuals with major depression, and in suicide completers with other psychiatric diagnoses . It is important to note, however, that these studies do not distinguish between soluble TNF and transmembrane TNF protein.…”