The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus,Cell

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The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus
Cell ( IF 64.5 ) Pub Date : 2023-02-16 , DOI: 10.1016/j.cell.2023.01.017
Stephanie M Robert ₁ , Benjamin C Reeves ₁ , Emre Kiziltug ₁ , Phan Q Duy ₁ , Jason K Karimy ₁ , M Shahid Mansuri ₂ , Arnaud Marlier ₁ , Garrett Allington ₃ , Ana B W Greenberg ₁ , Tyrone DeSpenza ₁ , Amrita K Singh ₁ , Xue Zeng ₁ , Kedous Y Mekbib ₁ , Adam J Kundishora ₁ , Carol Nelson-Williams ₁ , Le Thi Hao ₁ , Jinwei Zhang ₄ , TuKiet T Lam ₅ , Rashaun Wilson ₅ , William E Butler ₆ , Michael L Diluna ₁ , Philip Feinberg ₇ , Dorothy P Schafer ₈ , Kiavash Movahedi ₉ , Allen Tannenbaum ₁₀ , Sunil Koundal ₁₁ , Xinan Chen ₁₂ , Helene Benveniste ₁₁ , David D Limbrick ₁₃ , Steven J Schiff ₁ , Bob S Carter ₆ , Murat Gunel ₁ , J Marc Simard ₁₄ , Richard P Lifton ₁₅ , Seth L Alper ₁₆ , Eric Delpire ₁₇ , Kristopher T Kahle ₁₈

Affiliation

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.
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter EX1 2LU, UK.
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA; Keck MS & Proteomics Resource, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; Medical Scientist Training Program, UMass Chan Medical School, Worcester, MA 01655, USA.
Department of Neurobiology, Brudnick Neuropsychiatric Research Institute University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium.
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York City, NY 11794, USA.
Department of Anesthesiology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA.
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Neurosurgery, University of Maryland, School of Medicine, Baltimore, MD 21201, USA; Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA; Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Laboratory of Human Genetics and Genomics, the Rockefeller University, New York, NY 10065, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA; Department of Neurosurgery and Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

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.

中文翻译：

脉络丛将先天免疫与脑积水脑脊液失调联系起来

脉络丛 (ChP) 是血脑脊液 (CSF) 屏障和 CSF 的主要来源。由脑部感染或出血引起的后天性脑积水由于病理生物学不明确而缺乏药物治疗。我们对感染后脑积水 (PIH) 和出血后脑积水 (PHH) 模型的综合多组学研究表明，脂多糖和血液分解产物在 ChP-CSF 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 ChP 巨噬细胞引起，通过 TNF 受体相关激酶 SPAK 的磷酸化激活，导致 ChP 上皮细胞的 CSF 产生增加，SPAK 作为多细胞的调节支架-离子转运蛋白复合物。遗传或药理学免疫调节通过拮抗 SPAK 依赖性 CSF 分泌过多来预防 PIH 和 PHH。这些结果揭示了 ChP 是一种动态的、细胞异质的组织，具有高度调节的免疫分泌能力，扩展了我们对 ChP 免疫上皮细胞串扰的理解，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。

更新日期：2023-02-16

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