Transient manganese exposure reprograms bone marrow-derived macrophages toward a stable anti-inflammatory memory...

Manganese ions (Mn2+) are potent immunomodulatory agents that activate the cGAS-STING pathway. While their role as acute adjuvants is well-documented, the innate immune memory (trained immunity) signatures induced by Mn2+ remain unexplored. Using an in vitro priming-rest-challenge model, we demonstrate that transient Mn2+ stimulation induces a persistent anti-inflammatory state in bone marrow-derived macrophages (BMDMs). Unlike the immediate proinflammatory burst associated with Mn2+, Mn2+-trained BMDMs displayed a stable reduction in Il6, Il1b, Il12a, and Nos2 expression upon secondary LPS or LPS + IFN-γ challenge. Furthermore, Mn2+ training enhanced IL-4-driven Arg1 induction and suppressed MHC class II surface expression, antigen presentation pathways, and phagocytic capacity against Candida albicans. Mechanistically, this functional attenuation was independent of glycolysis but correlated with a broad downregulation of lipid metabolic pathways. These findings reveal a lineage-specific regulatory "brake" induced by manganese, providing critical insights for its application in immunotherapy.