PDF(Pubmed)
Abstract：
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with significant public health implications that arise following exposure to traumatic events. Recent studies highlight the involvement of immune dysregulation in PTSD, characterized by elevated inflammatory markers. However, the precise mechanisms underlying this immune imbalance remain unclear. Previous research has implicated friend leukemia virus integration 1 (FLI1), an erythroblast transformation-specific (ETS) transcription factor, in inflammatory responses in sepsis and Alzheimer\'s disease. Elevated FLI1 levels in peripheral blood mononuclear cells (PBMCs) have been linked to lupus severity. Yet, FLI1\'s role in PTSD-related inflammation remains unexplored. In our study, PBMCs were collected from Veterans with and without PTSD. We found significantly increased FLI1 expression in PBMCs from PTSD-afflicted Veterans, particularly in CD4+ T cells, with no notable changes in CD8+ T cells. Stimulation with LPS led to heightened FLI1 expression and elevated levels of inflammatory cytokines IL-6 and IFNγ in PTSD PBMCs compared to controls. Knockdown of FLI1 using Gapmers in PTSD PBMCs resulted in a marked reduction in inflammatory cytokine levels, restoring them to control group levels. Additionally, co-culturing PBMCs from both control and PTSD Veterans with the human brain microglia cell line HMC3 revealed increased inflammatory mediator levels in HMC3. Remarkably, HMC3 cells co-cultured with PTSD PBMCs treated with FLI1 Gapmers exhibited significantly lower inflammatory mediator levels compared to control Gapmer-treated PTSD PBMCs. These findings suggest that suppressing FLI1 may rebalance immune activity in PBMCs and mitigate microglial activation in the brain. Such insights could provide novel therapeutic strategies for PTSD.
摘要：
创伤后应激障碍（PTSD）是一种使人衰弱的精神疾病，在暴露于创伤事件后会产生重大的公共卫生影响。最近的研究强调了免疫失调参与创伤后应激障碍，以炎症标志物升高为特征。然而,这种免疫失衡的确切机制尚不清楚.先前的研究涉及朋友白血病病毒整合1（FLI1），一种成红细胞转化特异性（ETS）转录因子，在脓毒症和阿尔茨海默病的炎症反应中。外周血单核细胞（PBMC）中FLI1水平升高与狼疮严重程度有关。然而，FLI1在PTSD相关炎症中的作用仍未被探索。在我们的研究中,从有和没有PTSD的退伍军人收集PBMC。我们发现PTSD患者的PBMC中FLI1表达显着增加，特别是在CD4+T细胞中，CD8+T细胞无显著变化。与对照相比,用LPS刺激导致PTSDPBMC中FLI1表达增强和炎性细胞因子IL-6和IFNγ水平升高。在PTSDPBMC中使用Gapmers敲除FLI1导致炎性细胞因子水平显著降低，恢复到控制组水平。此外,来自对照和PTSD退伍军人的PBMC与人脑小胶质细胞HMC3共培养显示HMC3中的炎症介质水平增加。值得注意的是,与对照Gapmer处理的PTSDPBMC相比,与用FLI1Gapmer处理的PTSDPBMC共培养的HMC3细胞表现出显著更低的炎症介质水平。这些发现表明，抑制FLI1可能会重新平衡PBMC中的免疫活性并减轻大脑中的小胶质细胞激活。这些见解可以为PTSD提供新的治疗策略。
