Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE.

中文翻译：

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小胶质细胞通过消除脓毒症相关脑病中 C1q 标记的突触来介导神经认知缺陷

脓毒症相关脑病 (SAE) 是脓毒症严重且常见的并发症，可导致谵妄、昏迷和长期认知功能障碍。我们在脓毒症患者的海马尸检组织中发现了小胶质细胞和 C1q 补体激活，并在小鼠多种微生物脓毒症模型中增加了 C1q 介导的突触修剪。海马组织的无偏转录组学和来自败血症小鼠的分离的小胶质细胞揭示了先天免疫系统的参与、补体激活和溶酶体通路在 SAE 期间的上调与神经元和突触损伤平行。小胶质细胞吞噬 C1q 标记的突触可以通过立体定向海马内注射特定的 C1q 阻断抗体来防止。通过 PLX5622（一种 CSF1-R 抑制剂）进行药理学靶向小胶质细胞，降低 C1q 水平和 C1q 标记突触的数量，防止神经元损伤和突触丢失，并改善神经认知结果。因此，我们将小胶质细胞进行的补体依赖性突触修剪确定为 SAE 期间神经元缺陷发展的关键病理机制。