Li Pengfei, Liu Liu, Halushka Perry V, Trojanowska Maria, Wang Guirong, Ergul Adviye, Fan Hongkuan
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29425, USA.
Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.
Inflamm Res. 2025 Jan 25;74(1):28. doi: 10.1007/s00011-025-02000-z.
Sepsis-associated encephalopathy (SAE) often results from neuroinflammation. Recent studies have shown that brain platelet-derived growth factor receptor β (PDGFRβ) cells, including pericytes, may act as early sensors of infection by secreting monocyte chemoattractant protein-1 (MCP-1), which transmits inflammatory signals to the central nervous system. The erythroblast transformation-specific (ETS) transcription factor Friend leukemia virus integration 1 (Fli-1) plays a critical role in inflammation by regulating the expression of key cytokines, including MCP-1. However, the role of pericyte Fli-1 in neuroinflammation during sepsis remains largely unknown.
WT and pericyte-specific Fli-1 knockout mice were subjected to endotoxemia through LPS injection or sepsis via cecal ligation and puncture (CLP). In vitro, Fli-1 was knocked down using small interfering RNA in cultured mouse brain pericytes, followed by LPS stimulation.
Elevated Fli-1 levels were observed in isolated brain pericytes 2 h after LPS administration, in brain tissues 4 h after CLP, and in cultured mouse brain pericytes 2 h after LPS stimulation in vitro. In endotoxemic mice, pericyte-specific Fli-1 knockout reduced expression of MCP-1 and IL-6 in brain tissue 2 h after LPS injection. At 24 h post-LPS administration, protein levels of MCP-1 and IL-6, and microglia activation were suppressed in pericyte-Fli-1 knockout mice. Additionally, Fli-1 deficiency in pericytes significantly reduced MCP-1 and IL-6 mRNA levels in the brain tissue 4 h after CLP. Moreover, in cultured brain pericytes, Fli-1 knockdown markedly decreased MCP-1 and IL-6 levels after LPS stimulation. Notably, LPS stimulation increased Fli-1 levels via TLR4-Myd88 signaling, which subsequently led to elevated production of MCP-1 in brain pericytes.
Fli-1 in pericytes may serve as a crucial mediator of neuroinflammation during sepsis by directly regulating pivotal cytokines such as MCP-1 and IL-6. Therefore, Fli-1 has the potential to serve as a therapeutic target in SAE and other neuroinflammatory disorders.
脓毒症相关脑病（SAE）通常由神经炎症引起。最近的研究表明，包括周细胞在内的脑血小板衍生生长因子受体β（PDGFRβ）细胞可能通过分泌单核细胞趋化蛋白-1（MCP-1）作为感染的早期传感器，MCP-1将炎症信号传递至中枢神经系统。成红细胞转化特异性（ETS）转录因子Friend白血病病毒整合1（Fli-1）通过调节包括MCP-1在内的关键细胞因子的表达在炎症中起关键作用。然而，周细胞Fli-1在脓毒症期间神经炎症中的作用仍 largely 未知。
野生型和周细胞特异性Fli-1基因敲除小鼠通过注射脂多糖（LPS）诱导内毒素血症或通过盲肠结扎和穿刺（CLP）诱导脓毒症。在体外，使用小干扰RNA在培养的小鼠脑周细胞中敲低Fli-1，然后进行LPS刺激。
在LPS给药后2小时分离的脑周细胞中、CLP后4小时的脑组织中以及体外LPS刺激后2小时的培养小鼠脑周细胞中观察到Fli-1水平升高。在内毒素血症小鼠中，周细胞特异性Fli-1基因敲除降低了LPS注射后2小时脑组织中MCP-1和IL-6的表达。在LPS给药后24小时，周细胞Fli-1基因敲除小鼠中MCP-1和IL-6的蛋白水平以及小胶质细胞活化受到抑制。此外，周细胞中Fli-1缺乏显著降低了CLP后4小时脑组织中MCP-1和IL-6的mRNA水平。此外，在培养的脑周细胞中，Fli-1敲低显著降低了LPS刺激后MCP-1和IL-6的水平。值得注意的是，LPS刺激通过TLR4-Myd88信号通路增加了Fli-1水平，随后导致脑周细胞中MCP-1的产生增加。
周细胞中的Fli-1可能通过直接调节诸如MCP-1和IL-6等关键细胞因子而成为脓毒症期间神经炎症的关键介质。因此，Fli-1有潜力作为SAE和其他神经炎症性疾病的治疗靶点。
