Exosomal miR-132-3p derived from M1 macrophages mediates diffuse alveolar hemorrhage in systemic lupus erythematosus

Abstract Objective This study examines how exosomal miR-132-3p from M1 macrophages contributes to the development of systemic lupus erythematosus (SLE)-associated DAH and the molecular mechanisms involved. Methods A pristane-induced murine model of SLE-DAH was established, and mice received either a miR-132-3p antagomir or control. Parallel in vitro studies were conducted using human alveolar epithelial (A549) and human pulmonary microvascular endothelial cells (HPMECs) undergoing treatment with either miR-132-3p mimics or inhibitors. Barrier integrity, inflammation, apoptosis, and molecular signalling were evaluated using qRT-PCR, Western blotting, immunofluorescence, TEER measurement, FITC-dextran permeability, TUNEL assay, and dual-luciferase assays. Results Compared with controls, pristane-induced SLE-DAH mice exhibited pronounced pulmonary hemorrhage, lung weight gain, and alveolar damage, along with elevated inflammation-related cytokines (IL-6, TNF-α, IL-1β) and decreased immune-regulating mediators (IL-10, TGF-β) in BALF; these changes were alleviated by miR-132-3p antagomir. miR-132-3p was upregulated in M1 macrophages, exosomes, and recipient A549 and HPMEC cells in both models, and suppressed by antagomir or inhibitor. Its overexpression impaired barrier integrity by downregulating ZO-1, Occludin, and E-cadherin, reduced TEER, enhanced FITC-dextran permeability, and promoted apoptosis; all were reversed upon miR-132-3p inhibition. Meanwhile, SIRT1 was suppressed and NF-κB p65 and IκBα phosphorylation enhanced, with dual-luciferase assays confirming the direct interaction between miR-132-3p and SIRT1. Conclusion M1 macrophage-originated exosomal miR-132-3p promotes lung injury in SLE-associated DAH by impairing alveolar barrier integrity and enhancing inflammatory signalling via the SIRT1/NF-κB axis. Targeting miR-132-3p could offer a novel treatment option for SLE-DAH.