Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE. Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg−1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice. In the septic mice, cognitive function was impaired, the percentage of CD4+ T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the anti-inflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg−1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4+ T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4+ T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4+ T cells in cultured splenocytes from septic mice (P = 0.0021). Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4+ T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/anti-inflammatory homeostasis.

中文翻译：

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ProBDNF通过抑制脑膜CD4 + T细胞的免疫活性，促进小鼠败血症相关性脑病。

败血症相关性脑病（SAE）可增加败血病患者的死亡率，但其机制尚不清楚。本研究旨在研究T淋巴细胞，proBDNF及其在SAE发病机理中的相互作用。对脂多糖（LPS，5 mg kg-1）诱导的败血症小鼠进行了恐惧条件测试，以进行认知评估。收集脑膜和外周血用于流式细胞仪或qPCR。FTY720和单克隆抗proBDNF抗体（McAb-proB）被用于研究淋巴细胞耗竭和阻断proBDNF对败血症小鼠认知功能受损的影响。在败血病小鼠中，认知功能受损，脑膜（P = 0.0021）和循环（P = 0.0222）中CD4 + T细胞的百分比降低，促炎细胞因子被上调，但脑膜中的抗炎细胞因子白介素（IL）-4（P <0.0001）和IL-13（P = 0.0350）被下调。胃内处理的FTY720（1 mg kg-1）持续1周消除了淋巴细胞，改善了LPS诱导的学习缺陷。此外，proBDNF在脑膜（P = 0.0042）和外周（P = 0.0090）CD4 + T细胞中增加。LPS治疗前腹腔注射McAb-proB（100μg）可显着缓解认知功能障碍，抑制脑膜（P = 0.0264）和外周（P = 0.0080）CD4 + T细胞的下调，并使脑膜中细胞因子的基因表达正常化。但是，脑室内McAb-proB注射（1微克）没有这种作用。最后，外源性proBDNF下调脓毒症小鼠脾细胞中CD4 + T细胞的百分比（P = 0.0021）。