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

Introduction 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 anti-angiogenic properties is closely related to the destruction of the BBB. However, its role in the pathogenesis of NMOSD remains unclear. Methods An in vitro blood-brain barrier (BBB) model was established using a monolayer of hCMEC/D3 cells. We investigated the effects of plasma from patients with neuromyelitis optica spectrum disorder (NMOSD) on BBB permeability and microstructure. Additionally, the expression of AIMP1 and ZO-1 in human brain microvascular endothelial cells (BMECs) 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. Results 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. Conclusion In conclusion, 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.