Transient Manganese Exposure Reprograms Bone Marrow–Derived Macrophages Toward a Stable Anti-Inflammatory Memory State

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 (BMDM).

Unlike the immediate pro-inflammatory burst associated with Mn2+, Mn2+-trained BMDMs displayed a stable reduction in Il6, Il1b, Il12a, and Nos2 expression upon secondary LPS or LPS+IFNγ challenge. Furthermore, Mn2+ training enhanced IL-4-driven Arg1 induction and suppressed MHC 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.