背景:不变自然杀伤T(iNKT)细胞在多种免疫和炎性疾病中发挥保护或致病作用。然而,iNKT细胞是否有助于急性神经炎症的进展尚不清楚.因此,我们用脂多糖(LPS)诱导的急性神经炎症小鼠模型解决了这个问题。
方法:对于急性神经炎症的诱导,野生型(WT)C57BL/6(B6)小鼠腹膜内(腹膜内)注射LPS连续三天或五天,然后分析这些小鼠的脑浸润白细胞或小鼠行为,分别。探讨iNKT细胞活化在LPS诱导的神经炎症中的作用,在LPS处理前7天用iNKT细胞激动剂α-半乳糖基神经酰胺(α-GalCer)腹膜内注射小鼠。通过流式细胞术确定在LPS诱导的神经炎症期间浸润到大脑中的免疫细胞。此外,通过开放视野和Y-迷宫测试评估LPS诱导的小鼠的临床行为症状,例如抑郁样行为和记忆障碍。分别。
结果:我们发现,与WT小鼠相比,iNKT细胞缺陷型Jα18突变小鼠表现出疾病进展延迟和白细胞浸润减少,表明iNKT细胞参与了LPS诱导的神经炎症的发病机制。自从有报道用α-GalCer预处理以来,iNKT细胞激动剂,可以将iNKT细胞转化为抗炎表型,我们接下来探讨α-GalCer预激活iNKT细胞是否可以调节LPS诱导的神经炎症。引人注目的是,我们发现α-GalCer预处理显著延迟临床症状的发作,包括抑郁样行为和记忆障碍,同时减少促炎自然杀伤细胞和中性粒细胞的脑浸润,在LPS诱导的神经炎症模型中。α-GalCer预处理的这种抗炎作用与iNKT细胞向产生IL4-和IL10的表型极化密切相关。此外,α-GalCer预处理恢复了LPS诱导的神经炎症过程中脑调节性T细胞上抑制性标志物的表达。
结论:我们的发现提供了强有力的证据,表明α-GalCer诱导的iNKT细胞的预激活可扩增iNKT10细胞,减轻LPS诱导的急性神经炎症诱导的炎症免疫细胞的抑郁样行为和脑浸润。因此,我们建议iNKT细胞和α-GalCer预防急性神经炎症的潜力。
BACKGROUND: Invariant natural killer T (iNKT) cells play protective or pathogenic roles in a variety of immune and inflammatory diseases. However, whether iNKT cells contribute to the progression of acute neuroinflammation remains unclear. Thus, we addressed this question with a mouse model of lipopolysaccharide (LPS)-induced acute neuroinflammation.
METHODS: For induction of acute neuroinflammation, wild-type (WT) C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with LPS for either three or five consecutive days, and then these mice were analyzed for brain-infiltrating leukocytes or mouse behaviors, respectively. To examine the role of iNKT cell activation in LPS-induced neuroinflammation, mice were injected i.p. with the iNKT cell agonist α-galactosylceramide (α-GalCer) seven days prior to LPS treatment. Immune cells infiltrated into the brain during LPS-induced neuroinflammation were determined by flow cytometry. In addition, LPS-induced clinical behavior symptoms such as depressive-like behavior and memory impairment in mice were evaluated by the open field and Y-maze tests, respectively.
RESULTS: We found that iNKT cell-deficient Jα18 mutant mice display delayed disease progression and decreased leukocyte infiltration into the brain compared with WT mice, indicating that iNKT cells contribute to the pathogenesis of LPS-induced neuroinflammation. Since it has been reported that pre-treatment with α-GalCer, an iNKT cell agonist, can convert iNKT cells towards anti-inflammatory phenotypes, we next explored whether pre-activation of iNKT cells with α-GalCer can regulate LPS-induced neuroinflammation. Strikingly, we found that α-GalCer pre-treatment significantly delays the onset of clinical symptoms, including depression-like behavior and memory impairment, while decreasing brain infiltration of pro-inflammatory natural killer cells and neutrophils, in this model of LPS-induced neuroinflammation. Such anti-inflammatory effects of α-GalCer pre-treatment closely correlated with iNKT cell polarization towards IL4- and
IL10-producing phenotypes. Furthermore, α-GalCer pre-treatment restored the expression of suppressive markers on brain regulatory T cells during LPS-induced neuroinflammation.
CONCLUSIONS: Our findings provide strong evidence that α-GalCer-induced pre-activation of iNKT cells expands iNKT10 cells, mitigating depressive-like behaviors and brain infiltration of inflammatory immune cells induced by LPS-induced acute neuroinflammation. Thus, we suggest the prophylactic potential of iNKT cells and α-GalCer against acute neuroinflammation.