2. Academic Validation
  3. Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus

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

  • Acta Pharm Sin B. 2024 Oct;14(10):4544-4559. doi: 10.1016/j.apsb.2024.06.020.
Qiguang Wang 1,  Fei Liu 2,  Yue Li 3,  Huan Zhang 1,  Xin Qi 1,  Ke Wu 4,  Yi Zhang 3,  Shenglan You 3,  Wenke Liu 1,  Xuhui Hui 1,  Hanmei Li 5,  Lei Zhu 6,  Huile Gao 7,  Jian Cheng 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Research Core Facility of West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 5 Key Laboratory of Coarse Cereal Processing, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China.
  • 6 Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 7 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
PMID: 39525574 DOI: 10.1016/j.apsb.2024.06.020
Abstract

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.

Keywords

CCL2; CCR2; Cerebrospinal fluid hypersecretion; Choroid plexus; Crosstalk; Epithelial cells; Hydrocephalus; Macrophages.

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