Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China.
Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China; Department of Pathophysiology, Hunan University of Chinese Medicine, Changsha, 410000, PR China.
Biochem Biophys Res Commun. 2020 Dec 17;533(4):1519-1526. doi: 10.1016/j.bbrc.2020.10.084. Epub 2020 Nov 4.
Cognitive impairment, acute or long-term, is a common complication in patients with severe bacterial infection. However, the underlying mechanisms are not fully verified and effective medicine is not available in clinics. Interferon gamma (IFNγ) is a pivotal cytokine against infection and is believed to be a tune in homeostasis of cognitive function. Here, we collected blood and cerebrospinal fluid (CF) from human subjects and mice, and found that plasma and CF levels of IFNγ were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFNγ signaling was boosted in the hippocampus of mice after a challenge of lipopolysaccharide (LPS), which was accompanied with cognitive impairment and decline of neurogenesis. Deficiency of IFNγ or its receptor (IFNγR) dramatically attenuated microglia-induced A1 astrocytes and consequently restored neurogenesis and cognitive function in endotoxemia mice model. Using primary microglia, astrocytes and neurons, we found that IFNγ remarkably increased LPS-mediated release of TNFα and IL-1α in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFNγ promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFNγ would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection.
认知障碍，无论是急性还是慢性，都是严重细菌感染患者的常见并发症。然而，其潜在机制尚未完全证实，临床上也缺乏有效的治疗药物。干扰素 γ（IFNγ）是一种对抗感染的关键细胞因子，被认为是调节认知功能的平衡器。在这里，我们收集了人类和小鼠的血液和脑脊液（CSF），发现与健康对照组相比，脓毒症患者和内毒素攻击的小鼠的血浆和 CSF 中 IFNγ 的水平显著升高。在脂多糖（LPS）的刺激下，IFNγ 信号在小鼠的海马体中被增强，这伴随着认知障碍和神经发生的下降。IFNγ 或其受体（IFNγR）的缺失显著减弱了小胶质细胞诱导的 A1 型星形胶质细胞，并因此恢复了内毒素血症小鼠模型中的神经发生和认知功能。使用原代小胶质细胞、星形胶质细胞和神经元，我们发现 IFNγ 可显著增加 LPS 介导的小胶质细胞中 TNFα 和 IL-1α 的释放，并由此诱导星形胶质细胞向 A1 亚型转化，最终导致神经元损伤。因此，IFNγ 通过增强小胶质细胞诱导的 A1 型星形胶质细胞促进内毒素血症中的认知障碍。靶向 IFNγ 可能是预防或治疗革兰氏阴性菌感染患者认知功能障碍的一种新策略。
