Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus  

作　　者：Qiguang Wang Fei Liu Yue Li Huan Zhang Xin Qi Ke Wu Yi Zhang Shenglan You Wenke Liu Xuhui Hui Hanmei Li Lei Zhu Huile Gao Jian Cheng 

机构地区：[1]Department of Neurosurgery,West China Hospital,Sichuan University,Chengdu 610041,China [2]Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry,West China School of Pharmacy,Sichuan University,Chengdu 610041,China [3]Institute of Thoracic Oncology,West China Hospital,Sichuan University,Chengdu 610041,China [4]Institutes for Systems Genetics,Frontiers Science Center for Disease-Related Molecular Network,West China Hospital,Sichuan University,Chengdu 610041,China [5]Institute of Rare Diseases,West China Hospital of Sichuan University,Chengdu 610041,China [6]Research Core Facility of West China Hospital,Sichuan University,Chengdu 610041,China [7]Key Laboratory of Coarse Cereal Processing,School of Food and Biological Engineering,Chengdu University,Chengdu 610106,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4544-4559,共16页药学学报（英文版）

基　　金：the National Natural Science Foundation of China(82201501);the Natural Science Foundation of Sichuan Province(2023NSFC1581,China);1·3.5 projects for disciplines of excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University(No.2020HXFH013,China);Sichuan Science and Technology Program(22ZDYF2619,China)for financial support.

摘　　要：The choroid plexus(ChP)serves as the principal origin of cerebrospinal fluid(CSF).CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently.Nevertheless,the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined.In the present study,we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation.Specifically,we identify the chemokine CCL2,released by ChP epithelial cells,recruits CCR2+monocytes to the ChP thereby inciting hydrocephalus pathogenesis.The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade,thereby leading to CSF hypersecretion.Strikingly,augmentation of ChP‒CCL2 using an adeno-associated viral approach(AAV)exacerbates macrophage recruitment,activation,and ventriculomegaly in rat PHH models.Systemic application of Bindarit,a specific CCL2 inhibitor,significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate.Furthermore,the administration of CCR2 antagonist(INCB 3284)reduces ChP macrophage accumulation and ventriculomegaly.This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.

关 键 词：HYDROCEPHALUS MACROPHAGES CCL2 CCR2 Choroid plexus Epithelial cells CROSSTALK Cerebrospinal fluid hypersecretion 

分 类 号：R774.5[医药卫生—眼科] R318.08[医药卫生—临床医学]