Let-7f-5p/AIMP1/ZO-1 axis mediates blood-brain barrier dysfunction in neuromyelitis optica spectrum disorders.

Dysfunction of the blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of neuromyelitis optica spectrum disorders (NMOSD). AIMP1 as a novel proinflammatory factor with antiangiogenic properties is closely related to the destruction of the BBB. This study aimed to investigate whether AIMP1 contributes to BBB disruption and to explore the underlying regulatory mechanisms. An in vitro BBB model was established using a monolayer of hCMEC/D3 cells. We investigated the effects of plasma from patients with NMOSD on BBB permeability and microstructure. Additionally, the expression of AIMP1 and ZO-1 in human brain microvascular endothelial cells was examined by quantitative real-time PCR and western blot. A luciferase reporter assay was used to validate the targeting relationship between let-7f-5p and AIMP1. To further explore the role of AIMP1 in BBB permeability and its underlying molecular mechanisms, plasmid transfection was performed in hCMEC/D3 cells. Plasma from NMOSD patients significantly impaired BBB integrity, as shown by decreased endothelial cell viability, increased sodium fluorescein (Na-F) permeability, and disrupted tight junctions. AIMP1 expression was significantly upregulated (P < 0.001), while ZO-1 expression was downregulated (P < 0.001) in NMOSD plasma-treated cells. Knockdown of AIMP1 via siRNA restored ZO-1 protein levels (P = 0.011) and reduced BBB permeability (P = 0.018). Overexpression of AIMP1 led to opposite effects, further confirming its role in barrier dysfunction. A luciferase reporter assay demonstrated that miRNA let-7f-5p directly targets AIMP1. Overexpression of let-7f-5p in hCMEC/D3 cells suppressed AIMP1 expression and partially rescued ZO-1 levels, suggesting that let-7f-5p negatively regulates AIMP1-mediated BBB damage. AIMP1 contributes to BBB dysfunction in NMOSD by downregulating the tight junction protein ZO-1, and let-7f-5p may exert a protective effect by targeting AIMP1. These findings highlight a novel let-7f-5p/AIMP1/ZO-1 regulatory axis involved in BBB impairment, offering potential therapeutic implications for NMOSD.