背景:感染引起的认知功能障碍通常是败血症幸存者的并发症。然而,对其发病机制的全面了解仍然难以捉摸。
方法:在我们的体内实验中,采用内毒素血症动物模型,利用新型物体识别测试和莫里斯水迷宫测试来评估认知功能。各种技术,包括免疫荧光染色,西方印迹,血脑屏障通透性评估,LimulusAmebocyte裂解物(LAL)测定,和邻近连接测定,用于识别脑部病理损伤和神经炎症。为了辨别Caspase-11(Casp11)在内毒素血症诱导的认知衰退中的造血或非造血细胞中的作用,使用野生型(WT)和Casp11缺陷小鼠通过骨髓移植(BMT)产生骨髓嵌合体。体外研究涉及用大肠杆菌来源的外膜囊泡处理BV2细胞以模拟体内条件。
结果:我们的研究结果表明,Casp11-GSDMD信号通路的缺乏逆转了感染诱导的认知功能障碍。此外,认知功能障碍可以通过阻断IL-1的作用来改善。机械上,Casp11信号的缺失显著缓解了血脑屏障渗漏,小胶质细胞激活,海马CA3区的突触损伤,最终导致认知功能的改善。
结论:本研究揭示了Casp11和GSDMD对小鼠脓毒症模型中认知障碍和空间记忆丧失的重要贡献。针对Casp11信号传导成为预防或治疗严重感染患者认知功能障碍的有希望的策略。
BACKGROUND: Cognitive dysfunction caused by infection frequently emerges as a complication in sepsis survivor patients. However, a comprehensive understanding of its pathogenesis remains elusive.
METHODS: In our in vivo experiments, an animal model of endotoxemia was employed, utilizing the Novel Object Recognition Test and Morris Water Maze Test to assess cognitive function. Various techniques, including immunofluorescent staining, Western blotting, blood‒brain barrier permeability assessment, Limulus Amebocyte Lysate (LAL) assay, and Proximity-ligation assay, were employed to identify brain pathological injury and neuroinflammation. To discern the role of Caspase-11 (Casp11) in hematopoietic or non-hematopoietic cells in endotoxemia-induced cognitive decline, bone marrow chimeras were generated through bone marrow transplantation (BMT) using wild-type (WT) and Casp11-deficient mice. In vitro studies involved treating BV2 cells with E. coli-derived outer membrane vesicles to mimic in vivo conditions.
RESULTS: Our findings indicate that the deficiency of Casp11-GSDMD signaling pathways reverses infection-induced cognitive dysfunction. Moreover, cognitive dysfunction can be ameliorated by blocking the IL-1 effect. Mechanistically, the absence of Casp11 signaling significantly mitigated blood‒brain barrier leakage, microglial activation, and synaptic damage in the hippocampal CA3 region, ultimately leading to improved cognitive function.
CONCLUSIONS: This study unveils the crucial contribution of Casp11 and GSDMD to cognitive impairments and spatial memory loss in a murine sepsis model. Targeting Casp11 signaling emerges as a promising strategy for preventing or treating cognitive dysfunction in patients with severe infections.