Liraglutide prevents lupus-associated diffuse alveolar hemorrhage via inhibiting lymphocyte infiltration and promoting macrophage M2 polarization.

OBJECTIVES: This study aimed to explore the prophylactic and therapeutic role of liraglutide for lupus-associated diffuse alveolar hemorrhage (DAH). METHODS: A lupus-associated DAH model was established in 6-8-week-old female C57BL/6 mice via intraperitoneal injection of 0.5 mL pristane. Mice were randomized to receive daily intraperitoneal injections of either saline or liraglutide (2 mg/kg/day), starting either 14 days before or on the day of pristane injection, and continuing until 14 days post-injection. Body weight and blood glucose were monitored. Serum levels of anti-dsDNA, ANA, total IgM and IgG were quantified using ELISA. Lung tissues were collected for histopathological analysis with H&E and Prussian blue staining, respectively, characterization of different types of immune cells infiltration with flow cytometry (t-SNE for subset dimensionality reduction) and immunofluorescence, and quantification of protein levels with Western blot. RESULTS: Liraglutide significantly alleviated pulmonary hemorrhage, as evidenced by reduced lung wet weight, incidence of lung hemorrhage, pulmonary hemosiderin-laden macrophages, and total serum IgG, without affecting body weight or glucose. Mechanistically, liraglutide treatment reduced pulmonary infiltration of multiple T and B lymphocyte subsets (e.g., CD4, CD8, B220), while concurrently increasing alveolar macrophages and promoting M2 macrophage polarization. The phenotypic shift was demonstrated by increased M2 cell numbers, elevated CD206 expression, and downregulation of M1 marker CD86 and upregulation of M2 marker CD163 as confirmed at the protein level. CONCLUSION: Liraglutide treatment effectively ameliorates lupus-associated DAH, potentially through modulation of T cells, B cells, and macrophages polarization, offering a novel prophylactic and therapeutic strategy for this fatal complication of lupus.