LncRNA KCNQ1OT1 modulates M2 macrophage polarization and angiogenic signaling via the miR-142-3p/TRIM24 axis in...

Retinopathy of prematurity (ROP) is a major cause of childhood blindness, driven by hypoxia-induced VEGF overproduction. Anti-VEGF therapy has limitations including recurrence and potential side effects, highlighting the need for upstream interventions. M2 macrophages contribute to ROP pathogenesis, but the regulatory mechanisms controlling their polarization remain unclear.

We explored the regulatory interplay among lncRNA KCNQ1OT1, miR-142-3p, and TRIM24 in RAW264.7 and THP-1 macrophages, human retinal microvascular endothelial cells (HRMECs), and an oxygen-induced retinopathy (OIR) mouse model. Interactions were validated via dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Effects on macrophage polarization and endothelial function were assessed using flow cytometry, immunofluorescence, and proliferation, migration, and tube formation assays. OIR mice received AAV-mediated KCNQ1OT1 delivery, followed by retinal histology, immunostaining, cytokine measurements, TUNEL assays, RT-qPCR, and Western blot analyses.

KCNQ1OT1 acted as a competitive endogenous RNA to sequester miR-142-3p, partially relieving suppression of TRIM24 and attenuating STAT6-mediated M2 polarization. In macrophages, KCNQ1OT1 overexpression reduced M2 markers and VEGFA expression, diminishing pro-angiogenic effects on HRMECs. In OIR mice, AAV-KCNQ1OT1 delivery was associated with reduced retinal neovascularization, decreased M2 macrophage infiltration, and lower VEGFA and inflammatory cytokine levels.

The KCNQ1OT1/miR-142-3p/TRIM24 axis influences macrophage polarization and angiogenic signaling in ROP. While preliminary, these findings suggest that targeting this upstream regulatory network may complement existing VEGF-targeted therapies.