Interleukin-2 treatment ameliorates murine lupus diffuse alveolar hemorrhage with improvement in T cell subset imbalance

Abstract Objective This study evaluated the therapeutic efficacy and mechanism of interleukin-2 (IL-2) in a pristane-induced murine model of lupus-associated diffuse alveolar hemorrhage (DAH). Methods C57BL/6J mice received intraperitoneal pristane injection to induce lupus-like DAH. IL-2 was administered at varying doses. Disease severity, histopathological alterations, inflammatory infiltration, cytokine profiles, T cell subsets, and apoptosis were assessed using hematoxylin and eosin staining, immunohistochemistry, flow cytometry, ELISA, and TUNEL assays. Transcriptomic sequencing of lung tissue was performed to identify IL-2 treatment related molecular pathways. Results IL-2 treatment reduced the incidence and severity of DAH in a dose-dependent manner, with the 100,000 U dose achieving the best therapeutic effect. Treated mice exhibited improved weight maintenance, reduced lung weight, enhanced survival, ameliorated histopathological damage in the lungs with decreased pulmonary infiltration of F4/80+ macrophages and lowered levels of TNF-α, IL-6, IL-10, MIP-1, and SDF-1 in bronchoalveolar lavage fluid and peripheral blood. IL-2 treatment also increased CD4+ regulatory T cells, reduced effector T cells, improved the Treg/conventional T cells (Tcon) ratio, and corrected Th1/Th2 imbalance. Pulmonary apoptotic cell accumulation was also reduced. Transcriptomic analysis revealed that the IL-2 therapy corrected widespread gene expression abnormalities, suppressing pathways associated with inflammation, chemotaxis, adhesion, and innate immunity, while downregulating IL-6, TNF, IL-1, and Toll-like receptor signaling. Conclusion IL-2 treatment improved murine lupus-associated DAH by restoring T cell homeostasis, suppressing inflammatory cascades, and regulating apoptosis and transcriptomic networks. These findings underscore the potential of IL-2 as a therapeutic candidate for SLE-related DAH and provide novel mechanistic insights for translation.