Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis
Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis
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DOI：
10.1016/j.bbi.2020.11.010
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发表时间：
2021-02-16
影响因子：
15.1
通讯作者：
Kotani, Joji
中科院分区：
文献类型：
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作者：
Saito, Masafumi;Fujinami, Yoshihisa;Kotani, Joji
脓毒症相关性脑病(SAE)不仅增加发病率和死亡率，而且与脓毒症患者出院后长期的精神损害有关。最近的研究表明，这些精神障碍是由感染引起的神经炎症引起的。然而，T细胞在SAE和精神障碍发病机制中的作用尚不清楚。因此，在这项研究中，我们的目标是阐明免疫细胞，特别是T细胞，如何影响这些疾病的发展和恢复。在盲肠悬浮液(CS)诱导的脓毒症小鼠模型上，我们进行了三种不同的行为测试，即旷场实验、大理石埋藏实验和强迫游泳实验，并观察了脓毒症小鼠的焦虑样行为。此外，脓毒症发作10天后，脓毒症小鼠脑内IL-1β和IL-6的表达水平以及中性粒细胞和T细胞的浸润也被检测到。脓毒症发病20天后，脓毒症小鼠星形胶质细胞数量基本恢复。在第30天，脓毒症小鼠大脑皮层中IL-1β和肿瘤坏死因子-α的表达水平恢复到正常水平。有趣的是，FTY720治疗的脓毒症小鼠神经炎症的消退和抑郁的缓解被推迟，FTY720抑制了依赖鞘氨醇-1-磷酸(S1P)的淋巴细胞从淋巴中输出。在分析使用或不使用FTY720的脓毒症小鼠的脑T细胞时，未治疗FTY720的小鼠大脑中调节性T细胞(Treg)和Th2细胞增加，而治疗FTY720的小鼠在第30天显示大脑中Th17细胞增加。此外，在FTY720治疗的脓毒症小鼠中，大脑皮层中的星形胶质细胞数量在第30天仍然减少。这些结果提示，在脓毒症慢性期，浸润的Treg和Th2细胞有助于减轻SAE，减轻SAE所致的精神障碍。
Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1 beta and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1 beta and tumor necrosis factor (TNF)-alpha returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis.