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Published on: January 7, 2019
Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock
Yanchao Gu1, Jingjing Tang1, Fuhua Zhang1
1State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling 712100, Shaanxi, China.
Abstract:
Divalent metal ions such as magnesium (Mg2+), manganese (Mn2+), and zinc (Zn2+) play important roles in regulating innate immune responses. Lipopolysaccharide stimulation led to increased intracellular Mn and Zn in macrophages. However, the effect of those metal ions in regulating lipopolysaccharide-induced innate immune responses remains unclear. Here, we uncovered that both Mn2+ and Zn2+ have immunostimulatory effects, which could potentiate the lipopolysaccharide-induced expression of interferon-stimulated genes (ISGs), cytokines and pro-inflammatory genes in a dose-dependent manner. Enhancement of lipopolysaccharide-induced innate immune gene expression by Mn2+ varies between 10 % and 900 %. Conversely, the chelating of Mn2+ almost totally diminished Mn2+-enhanced lipopolysaccharide-induced gene expression. In addition, Mn2+ exerted its ability to potentiate LPS-induced innate immune gene expression regardless of slight pH changes. Importantly, we found that Mn2+ potentiates lipopolysaccharide-induced immune responses independent of TLR4 but partially relies on cGAS-STING pathway. Further in vivo study showed that colloidal Mn2+ salt (Mn jelly [MnJ]) pretreatment exacerbated lipopolysaccharide-induced septic shock and mice death. In conclusion, we demonstrated that Mn2+ plays an essential role in boosting lipopolysaccharide-induced innate immune responses. These findings greatly expand the current understanding of the immunomodulatory potential of divalent metal Mn2+ and may provide a potential therapeutic target to prevent excessive immune responses.
Insights
Manganese (Mn2+) and zinc (Zn2+) ions boost innate immune responses to lipopolysaccharide (LPS). Mn2+ potentiates LPS-induced gene expression and worsens septic shock, highlighting its role in immune regulation.
Area of Science:
- Immunology
- Inorganic Chemistry
- Molecular Biology
Background:
- Divalent metal ions like magnesium (Mg2+), manganese (Mn2+), and zinc (Zn2+) are crucial for innate immunity.
- Lipopolysaccharide (LPS) stimulation increases intracellular Mn2+ and Zn2+ in macrophages.
- The precise role of these metal ions in modulating LPS-induced immune responses is not fully understood.
Purpose of the Study:
- To investigate the effects of Mn2+ and Zn2+ on lipopolysaccharide-induced innate immune responses.
- To elucidate the mechanisms underlying Mn2+'s potentiation of LPS-induced immune gene expression.
- To assess the in vivo impact of Mn2+ on LPS-induced septic shock.
Main Methods:
- Cellular assays measuring gene expression (ISGs, cytokines, pro-inflammatory genes) in response to LPS and metal ions.
- Metal ion chelation experiments to confirm the role of Mn2+.
- Analysis of Mn2+'s effect independent of pH and its pathway involvement (TLR4, cGAS-STING).
- In vivo studies using mice pretreated with colloidal Mn2+ salt (Mn jelly [MnJ]) followed by LPS challenge.
Main Results:
- Both Mn2+ and Zn2+ demonstrated immunostimulatory effects, dose-dependently potentiating LPS-induced gene expression.
- Mn2+ enhancement ranged from 10% to 900%, and its removal via chelation nearly abolished this effect.
- Mn2+ potentiated LPS responses independently of TLR4 but partially relied on the cGAS-STING pathway.
- In vivo, Mn2+ pretreatment exacerbated LPS-induced septic shock and mortality.
Conclusions:
- Mn2+ plays a significant role in amplifying LPS-induced innate immune responses.
- These findings expand the understanding of Mn2+'s immunomodulatory potential.
- Mn2+ may represent a therapeutic target for managing excessive immune responses.
