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Published on: August 11, 2023
Manganese modulates pro-inflammatory gene expression in activated glia
Chun-Jung Chen1, Yen-Chuan Ou, Shih-Yi Lin
1Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan. cjchen@vghtc.gov.tw
Abstract:
Redox-active metals are of paramount importance for biological functions. Their impact and cellular activities participate in the physiological and pathophysiological processes of the central nervous system (CNS), including inflammatory responses. Manganese is an essential trace element and it is required for normal biological activities and ubiquitous enzymatic reactions. However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes, representative CNS immune cells. In this study, we assessed the molecular basis of the effects of manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it potentiated iNOS and TNF-alpha gene expression by lipopolysaccharide/interferon-gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese, generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-kappaB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IkappaB-alpha was one of underlying mechanisms for the increased activation of NF-kappaB by manganese. However, manganese decreased iNOS enzymatic activity possibly through the depletion of cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate that manganese could modulate glial inflammation through variable strategies.
Insights
Manganese exposure can worsen central nervous system inflammation by boosting pro-inflammatory responses in glial cells. This study reveals how manganese affects glial cells, impacting neuroinflammation and potential neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Redox-active metals, like manganese, are crucial for biological functions but excessive exposure can lead to neurotoxicity.
- Manganese neurotoxicity is linked to the activation of microglia and astrocytes, the primary immune cells in the central nervous system (CNS).
Purpose of the Study:
- To investigate the molecular mechanisms by which manganese affects pro-inflammatory cytokine and nitric oxide (NO) production in primary rat cortical glial cells.
- To understand manganese's role in modulating glial inflammatory responses.
Main Methods:
- Primary rat cortical glial cells (85% astrocytes, 15% microglia) were cultured and exposed to varying manganese concentrations.
- Cells were stimulated with lipopolysaccharide/interferon-gamma to assess manganese's effect on pro-inflammatory cytokine and nitric oxide synthase expression and activity.
- Molecular analyses included gene expression, protein activation (MAPK, NF-κB, AP-1), and cofactor activity assays.
Main Results:
- Manganese alone did not induce tumor necrosis factor alpha (TNF-α) or inducible nitric oxide synthase (iNOS) expression at tested concentrations.
- Manganese potentiated lipopolysaccharide/interferon-gamma-induced iNOS and TNF-α gene expression in glial cells.
- This potentiation was associated with increased free manganese, oxidative stress, mitogen-activated protein kinase activation, and enhanced NF-κB and AP-1 binding activity, partly via IκB-α degradation.
- Manganese decreased iNOS enzymatic activity, which was reversed by tetrahydrobiopterin, suggesting cofactor depletion.
Conclusions:
- Manganese exposure can modulate glial inflammation by enhancing pro-inflammatory responses and affecting nitric oxide production.
- The study highlights complex molecular strategies through which manganese influences neuroinflammation, involving oxidative stress and transcription factor activation.
- Findings suggest manganese's role in neurotoxicity may be mediated through its impact on glial inflammatory pathways.
