Cai Hanxiao, Huang Wenmian, Li Yicheng, Du Yutao, Ye Fanfan, Liu Tao, Yang Yiyi, Xue Xiaochang, Feng Guodong
Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, PR China.
Department of Experimental Medical Science, Experimental Neuroinflammation Laboratory, Lund University, Sölvegatan 19, Lund, 22362, Sweden.
Microb Pathog. 2025 Sep;206:107752. doi: 10.1016/j.micpath.2025.107752. Epub 2025 May 27.
The incidence of parameningeal infection (PI) is increasing in the context of therapy-induced immunosuppression. PI often presents with atypical symptoms, leading to delayed diagnosis and intervention, and can result in severe neurological sequelae. However, current understanding of PI remains limited due to a lack of basic research on host-pathogen interactions. Here, we first established a transient PI model in immunocompetent adult mice by intranasally administering Escherichia coli (E. coli), without inducing bacteraemia or systemic infection. When dexamethasone, an immunosuppressive and anti-inflammatory agent, was co-administered, the model transitioned into a prolonged state. Immunofluorescence and flow cytometry analyses revealed that dexamethasone prolonged PI by impairing innate immune-mediated clearance of E. coli at the skull bone marrow-dura mater border, which we identified as the initial immune barrier of the central nervous system (CNS). Specifically, dexamethasone inhibited the proliferation of Ly6C monocytes in the skull bone marrow and subsequently their influx to the dura mater, while also suppressing the functional shift of macrophages. These effects collectively hindered pathogen clearance and prolonged PI. Overall, our work established both transient and prolonged PI mouse models and explored how dexamethasone promotes PI progression. Our findings highlight the skull bone marrow-dura mater border as a critical frontline defence of the CNS, offering a potential target for the prophylaxis and therapy of PI and other CNS infections.
在治疗引起的免疫抑制背景下，脑膜旁感染（PI）的发病率正在上升。PI通常表现为非典型症状，导致诊断和干预延迟，并可能导致严重的神经后遗症。然而，由于缺乏对宿主-病原体相互作用的基础研究，目前对PI的了解仍然有限。在此，我们首先通过鼻内给予大肠杆菌（E. coli）在免疫功能正常的成年小鼠中建立了一个短暂性PI模型，且未诱发菌血症或全身感染。当联合使用免疫抑制和抗炎药物地塞米松时，该模型转变为持续状态。免疫荧光和流式细胞术分析显示，地塞米松通过损害颅骨骨髓-硬脑膜边界处先天免疫介导的大肠杆菌清除，延长了PI，我们将该边界确定为中枢神经系统（CNS）的初始免疫屏障。具体而言，地塞米松抑制了颅骨骨髓中Ly6C单核细胞的增殖，随后抑制了它们向硬脑膜的流入，同时还抑制了巨噬细胞的功能转变。这些作用共同阻碍了病原体清除并延长了PI。总体而言，我们的工作建立了短暂性和持续性PI小鼠模型，并探索了地塞米松如何促进PI进展。我们的研究结果突出了颅骨骨髓-硬脑膜边界作为CNS的关键前沿防御，为PI和其他CNS感染的预防和治疗提供了一个潜在靶点。
