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Transient Manganese Exposure Reprograms Bone Marrow–Derived Macrophages Toward a Stable Anti-Inflammatory Memory State [CUT&Tag]

ABSTRACT: 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 (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. These findings reveal a lineage-specific regulatory "brake" induced by manganese, providing critical insights for its application in immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE342686 | GEO | 2026/09/04

REPOSITORIES: GEO

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

Project description: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 (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. These findings reveal a lineage-specific regulatory "brake" induced by manganese, providing critical insights for its application in immunotherapy.

2026-09-04 | GSE316743 | GEO

Manganese (II) Activates cGAS-STING pathway

Project description:We show that Manganese (II) is a potent type I-IFN inducing agonist, stimulating cells into an anti-viral state in the absence of infection. Mechanically, Mn2+ treatment led to a profound cGAS-STING-dependent innate immune activation, conferring cells or mice viral resistance.

2018-10-09 | GSE77216 | GEO

Comparison of expression profiles for Agrobacterium tumefaciens wild-type strain C58 grown with or without manganese

Project description:The plant pathogen Agrobacterium tumefaciens attaches to and forms biofilms on both biotic and abiotic surfaces. The transition between free-living, planktonic A. tumefaciens and multicellular biofilms is regulated by several well-defined environmental and nutritional inputs, including pH, oxygen tension, and phosphate concentration. In many bacterial species limiting iron levels inhibit attachment and biofilm formation. In several systems intracellular levels of the redox-active manganous (Mn2+) and ferrous (Fe2+) ions are interrelated and have tight corresponding regulation with respect to one another. We show that limiting manganese concentrations elicit similar growth and biofilm phenotypes to those seen under iron-limiting conditions. Microarray analysis comparing gene expression in manganese-replete versus manganese-limiting conditions identified a small number of differentially regulated transcripts. These results indicate that the redox-active manganous and ferrous ions are required for wild-type levels of growth and biofilm formation, and that the manganese-dependent response is primarily post-transcriptional and complementary to, but not redundant with, the iron-dependent response. Four biological replicates, independent RNA preparations, two dye swaps.

2015-07-24 | E-GEOD-71266 | biostudies-arrayexpress

Comparison of expression profiles for Agrobacterium tumefaciens wild-type strain C58 grown with or without manganese

2015-07-24 | GSE71266 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of Manganese (II) or LPS treated Wild Type BMDC Transcriptomes

Project description:Purpose: The goals of this study are to compare the different functions of manganese (II) and LPS on the activation and maturation of antigen presenting cells-BMDCs. Methods: BMDCs were generated by culturing bone marrow cells with 20 ng/ml of IL-4 (Genscript) and 20 ng/ml of GM-CSF (Genscript) at 37°C and 5% CO2 for 7 days.Then BMDCs were treated with MnCl2 (200 μM) or LPS (100 ng/ml) for 20 h. Then mRNAs were purified, sequenced and analyzed. Results: Using an optimized data analysis workflow, we compared 20339 transcripts in BMDCs. Manganese (II) induced 1677 transcripts expression with a fold change ≥1.5 and LPS induced 1555 transcripts expression with a fold change ≥1.5. Conclusion: Manganese (II) activates the production of type I IFNs and the maturation of BMDCs. But there are also some differences between functions of manganese (II) and LPS on BMDCs.

2021-05-12 | GSE126586 | GEO

B. japonicum USDA110 low manganese vs. high manganese

Project description:Transcriptional profiling of B. japonicum manganese responsive cells and mur mutant responsive cells 3 independent biological materials were prepared for Wt manganese deplete, replete cultured cells and mur mutant manganese replete cultured cells

2011-08-24 | E-GEOD-30932 | biostudies-arrayexpress

Expanding the Pathways of Manganese Homeostasis: Role of a Small Manganese Chaperone Protein, MntS

Project description:Escherichia coli possesses >65 small proteins of <50 amino acids, many of which are uncharacterized. We have identified a new small protein, MntS, involved in manganese homeostasis. Manganese is a critical micronutrient, serving as an enzyme cofactor and protecting against oxidative stress. Yet manganese is toxic in excess and little is known about its function in cells. Bacteria carefully control intracellular manganese levels using the transcription regulator MntR. Before this work, mntH, which encodes a manganese importer, was the only gene known to respond to manganese via MntR repression in E. coli K12. We demonstrated that mntS is another member of the MntR manganese regulon. We also identified yebN, which encodes a putative manganese efflux pump, as the first gene positively regulated by MntR in Enterobacteria. Since MntS is expressed when manganese levels are low, causes manganese sensitivity when overexpressed, and binds manganese, we propose that MntS may be a manganese chaperone. This study reveals new factors involved in manganese regulation and metabolism and expands our knowledge of how small proteins function. Two E. coli strains, MG1655 (wild type) and GSO458 (Delta-mntR) were grown to OD600 ~ 0.5 in M9 glucose media at 37 M-BM-:C and treated with 10 microM MnCl2. In the first experiment, this incubation with 10 microM MnCl2 was for 60 min and in the second experiment, it was for 10 min. RNA was extracted using the hot phenol method and cDNA prepared and hybridized according the manufacturer's instructions (Affymetrix).

2011-12-08 | E-GEOD-25318 | biostudies-arrayexpress

Expanding the Pathways of Manganese Homeostasis: Role of a Small Manganese Chaperone Protein, MntS

2011-12-08 | GSE25318 | GEO

B. japonicum USDA110 low manganese vs. high manganese

Project description:Transcriptional profiling of B. japonicum manganese responsive cells and mur mutant responsive cells

2011-08-25 | GSE30932 | GEO

Gene expression in manganese-pretreated DNA-stimulated human macrophages

Project description:A total of 1,302 genes with greater than two-fold increase or decrease and p value less than 0.05 were included in the analysis. 582 genes (cluster 1) were downregulated by Mn2+, and 587 genes (cluster 2) were upregulated by Mn2+. A total of 133 genes (cluster 3) were upregulated by DNA transfection alone. The Venn diagram showed that 351 genes are upregulated in DNA-mediated responses and 247 genes were upregulated by Mn2+ treatment. Of note, the expression of 104 genes were initiated by DNA stimulation alone and then enhanced by Mn2+ treatments. Using a functional enrichment analysis resource (Metascape ), the set of 247 genes (Mn2+-treatment-mediated upregulation) was significantly enriched for the genes involved in multiple biological processes, such as innate immune response and inflammatory cytokines, which include IL-10, IL-4, and IL-13 signaling and the Toll-like receptor signaling pathway. Meanwhile, we noticed that Mn2+ treatment significantly enhanced the responses of the host cells to external stimuli. Similarly, the set of 104 genes was significantly enriched for cytokine signaling in the immune system and for responses to tumor necrosis factor (TNF) or IFN-γ. More interestingly, we found that both functional enrichment analyses for the 247 and 104 genes shared a common category: 38 genes in the 247 genes and 20 genes of the 104 genes were involved in the positive regulation of protein phosphorylation.

2022-09-27 | GSE214181 | GEO

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