The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus Journal Article
| Authors: | Robert, S. M.; Reeves, B. C.; Kiziltug, E.; Duy, P. Q.; Karimy, J. K.; Mansuri, M. S.; Marlier, A.; Allington, G.; Greenberg, A. B. W.; DeSpenza, T. Jr; Singh, A. K.; Zeng, X.; Mekbib, K. Y.; Kundishora, A. J.; Nelson-Williams, C.; Hao, L. T.; Zhang, J.; Lam, T. T.; Wilson, R.; Butler, W. E.; Diluna, M. L.; Feinberg, P.; Schafer, D. P.; Movahedi, K.; Tannenbaum, A.; Koundal, S.; Chen, X.; Benveniste, H.; Limbrick, D. D. Jr; Schiff, S. J.; Carter, B. S.; Gunel, M.; Simard, J. M.; Lifton, R. P.; Alper, S. L.; Delpire, E.; Kahle, K. T. |
| Article Title: | The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus |
| Abstract: | 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. © 2023 Elsevier Inc. |
| Keywords: | adult; controlled study; protein phosphorylation; unclassified drug; genetics; disease course; nonhuman; pathophysiology; animal cell; metabolism; animal tissue; animal experiment; animal model; enzyme activation; toll like receptor 4; brain; cerebrospinal fluid; rat; blood brain barrier; blood-brain barrier; epithelium cell; lipopolysaccharide; innate immunity; immunity, innate; immunomodulation; tumor necrosis factor receptor; macrophage; phosphotransferase; hydrocephalus; blood flow velocity; cerebrospinal fluid flow; choroid plexus; csf; cytokine storm; pharmacological parameters; humans; human; male; female; article; neuro-inflammation; multiomics; blood-csf barrier; nkcc1; spak; protein spak; cerebrospinal fluid abnormality; post infectious hydrocephalus |
| Journal Title: | Cell |
| Volume: | 186 |
| Issue: | 4 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2023-02-16 |
| Start Page: | 764 |
| End Page: | 785.e21 |
| Language: | English |
| DOI: | 10.1016/j.cell.2023.01.017 |
| PUBMED: | 36803604 |
| PROVIDER: | scopus |
| PMCID: | PMC10069664 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2023 -- Source: Scopus |
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