Targeting IL-1β to inhibit neutrophil extracellular traps improves meningeal lymphatic dysfunction in cerebral venous sinus thrombosis.

Abstract

Cerebral venous sinus thrombosis (CVST) is a rare but serious cerebrovascular disorder. Although meningeal lymphatic vessels (MLVs) play a critical role in cerebrospinal fluid (CSF) clearance and neuroimmune regulation, their contribution to CVST pathophysiology remains unclear. Here, we established a FeCl-induced CVST mouse model to investigate the role of MLV dysfunction. CVST mice exhibited impaired lymphatic drainage and neurological deficits. Ligation of MLVs further aggravated brain damage, and RNA-seq analysis identified activation of the IL-1β pathway as a key contributor. Mechanistically, neutrophils infiltrated MLVs in CVST mice and released neutrophil extracellular traps (NETs), which potentially contributing to lymphatic vessel apoptosis and reduced clearance efficiency. Therapeutic disruption of NETs with DNase I or the blockade of IL-1β signaling with IL-1 receptor antagonist (IL-1RA) preserved MLV integrity, improved CSF clearance, and ameliorated brain injury and behavioral impairments in CVST mice. Together, these findings identify the IL-1β-NET axis as a critical mediator of MLV dysfunction in CVST and highlight potential therapeutic targets to mitigate brain injury.