The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Robert Stephanie M, Reeves Benjamin C, Kiziltug Emre, Duy Phan Q, Karimy Jason K, Mansuri M Shahid, Marlier Arnaud, Allington Garrett, Greenberg Ana B W, DeSpenza Tyrone, Singh Amrita K, Zeng Xue, Mekbib Kedous Y, Kundishora Adam J, Nelson-Williams Carol, Hao Le Thi, Zhang Jinwei, Lam TuKiet T, Wilson Rashaun, Butler William E, Diluna Michael L, Feinberg Philip, Schafer Dorothy P, Movahedi Kiavash, Tannenbaum Allen, Koundal Sunil, Chen Xinan, Benveniste Helene, Limbrick David D, Schiff Steven J, Carter Bob S, Gunel Murat, Simard J Marc, Lifton Richard P, Alper Seth L, Delpire Eric, Kahle Kristopher T
Аннотация
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.