2023年2月16日出版的《细胞》杂志发表了美国科学家的一项最新研究成果。来自哈佛大学的Kristopher T. Kahle团队发现，脉络膜丛将先天免疫与脑积水脑脊液失调联系起来。
据研究人员介绍，脉络膜丛（ChP）是血-脑脊液（CSF）的屏障，并且是脑脊液的主要组成部分。获得性脑积水，由脑感染或出血引起，由于病理不明，缺乏药物治疗。
研究人员对感染后脑积水（PIH）和出血性脑积水（PHH）模型的综合、多组学研究显示，脂多糖和血液分解产物在ChP-CSF界面上引发高度相似的TLR4依赖性免疫反应。由此产生的CSF“细胞运动风暴”，由外周衍生和边界相关的ChP巨噬细胞引发，通过TNF受体相关激酶SPAK的磷酸化激活（SPAK作为多离子转运蛋白复合物的调节支架），增加了ChP上皮细胞的CSF产量。遗传或药理学免疫调节通过拮抗SPAK依赖的CSF高分泌来预防PIH和PHH。这些结果揭示了ChP是一种动态的、细胞异质性的组织，具有高度调节的免疫分泌能力，扩展了人们对ChP免疫上皮细胞的相互作用的理解，并将PIH和PHH重新定义为易受小分子药物治疗影响的相关神经免疫疾病。
附：英文原文
Title: The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus
Author: Stephanie M. Robert, Benjamin C. Reeves, Emre Kiziltug, Phan Q. Duy, Jason K. Karimy, M. Shahid Mansuri, Arnaud Marlier, Garrett Allington, Ana B.W. Greenberg, Tyrone DeSpenza, Amrita K. Singh, Xue Zeng, Kedous Y. Mekbib, Adam J. Kundishora, Carol Nelson-Williams, Le Thi Hao, Jinwei Zhang, TuKiet T. Lam, Rashaun Wilson, William E. Butler, Michael L. Diluna, Philip Feinberg, Dorothy P. Schafer, Kiavash Movahedi, Allen Tannenbaum, Sunil Koundal, Xinan Chen, Helene Benveniste, David D. Limbrick, Steven J. Schiff, Bob S. Carter, Murat Gunel, J. Marc Simard, Richard P. Lifton, Seth L. Alper, Eric Delpire, Kristopher T. Kahle
Issue&Volume: 2023/02/16
Abstract: The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primarysource of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacksdrug treatments due to obscure pathobiology. Our integrated, multi-omic investigationof post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) modelsrevealed that lipopolysaccharide and blood breakdown products trigger highly similarTLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF “cytokinestorm”, elicited from peripherally derived and border-associated ChP macrophages,causes increased CSF production from ChP epithelial cells via phospho-activation ofthe TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold ofa multi-ion transporter protein complex. Genetic or pharmacological immunomodulationprevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These resultsreveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulatedimmune-secretory capacity, expand our understanding of ChP immune-epithelial cellcross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable tosmall molecule pharmacotherapy.
DOI: 10.1016/j.cell.2023.01.017
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00047-8