Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017.
The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.
脉络丛（ChP）是血脑屏障和脑脊液（CSF）的主要来源。由脑感染或出血引起的获得性脑积水由于病理生理学不明确，缺乏药物治疗。我们对感染后性脑积水（PIH）和出血后性脑积水（PHH）模型进行了综合的多组学研究，结果表明脂多糖和血液分解产物在脉络丛-脑脊液界面触发高度相似的 TLR4 依赖性免疫反应。由此产生的 CSF“细胞因子风暴”，由外周来源和边界相关的脉络丛巨噬细胞引发，通过 TNF 受体相关激酶 SPAK 的磷酸化激活，导致脉络丛上皮细胞产生更多的 CSF，SPAK 作为多离子转运蛋白复合物的调节支架。遗传或药物免疫调节通过拮抗 SPAK 依赖性 CSF 过度分泌来预防 PIH 和 PHH。这些结果揭示了脉络丛是一种具有高度调节免疫分泌能力的动态、细胞异质性组织，扩展了我们对脉络丛免疫上皮细胞相互作用的理解，并将 PIH 和 PHH 重新定义为易受小分子药物治疗的相关神经免疫疾病。
