Sepsis-associated encephalopathy (SAE) is a clinical syndrome of brain dysfunction secondary to sepsis, which is characterized by long-term neurocognitive deficits such as memory, attention, and executive dysfunction. However, the mechanisms underlying SAE remain unclear. By using transcriptome sequencing approach, we showed that hippocampal S100A9 was significantly increased in sepsis induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. Thus, we used S100A9 inhibitor Paquinimod to study the role of S100A9 in cognitive impairments in CLP-induced and LPS-induced mice models of SAE. Sepsis survivor mice underwent behavioral tests or the hippocampal tissues subjected to Western blotting, real-time quantitative PCR, and immunohistochemistry. Our results showed that CLP-induced and LPS-induced memory impairments were accompanied with increased expressions of hippocampal microglia Iba1 and CD86 (M1 markers), but reduced expression of Arg1 (M2 marker). Notably, S100A9 inhibition significantly improved the survival rate and learning and memory impairments in sepsis survivors, with a shift from M1 to M2 phenotype. Taken together, our study suggests that S100A9 upregulation might contribute to learning and memory impairments by promoting microglia M1 polarization in sepsis survivors, whereas S100A9 inhibition might provide a potential therapeutic target for SAE.

脓毒症相关脑病 (SAE) 是一种继发于脓毒症的脑功能障碍的临床综合征，其特征是长期的神经认知缺陷，如记忆力、注意力和执行功能障碍。然而，SAE 的潜在机制仍不清楚。通过使用转录组测序方法，我们发现海马 S100A9 在盲肠结扎和穿刺 (CLP) 或脂多糖 (LPS) 攻击诱导的败血症中显着增加。因此，我们使用 S100A9 抑制剂 Paquinimod 来研究 S100A9 在 CLP 诱导和 LPS 诱导的 SAE 小鼠模型认知障碍中的作用。脓毒症幸存者小鼠接受行为测试或海马组织接受蛋白质印迹、实时定量 PCR 和免疫组织化学。我们的结果表明，CLP 诱导和 LPS 诱导的记忆障碍伴随着海马小胶质细胞 Iba1 和 CD86（M1 标记）的表达增加，但 Arg1（M2 标记）的表达降低。值得注意的是，S100A9 抑制显着提高了败血症幸存者的存活率和学习记忆障碍，并从 M1 表型转变为 M2 表型。总之，我们的研究表明，S100A9 上调可能通过促进脓毒症幸存者的小胶质细胞 M1 极化而导致学习和记忆障碍，而 S100A9 抑制可能为 SAE 提供潜在的治疗靶点。S100A9 抑制显着提高了败血症幸存者的存活率和学习记忆障碍，从 M1 表型转变为 M2 表型。总之，我们的研究表明，S100A9 上调可能通过促进脓毒症幸存者的小胶质细胞 M1 极化而导致学习和记忆障碍，而 S100A9 抑制可能为 SAE 提供潜在的治疗靶点。S100A9 抑制显着提高了败血症幸存者的存活率和学习记忆障碍，从 M1 表型转变为 M2 表型。总之，我们的研究表明，S100A9 上调可能通过促进脓毒症幸存者的小胶质细胞 M1 极化而导致学习和记忆障碍，而 S100A9 抑制可能为 SAE 提供潜在的治疗靶点。