Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock.

Divalent metal ions such as magnesium (Mg ²⁺ ), manganese (Mn ²⁺ ), and zinc (Zn ²⁺ ) 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 Mn ²⁺ and Zn ²⁺ 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 Mn ²⁺ varies between 10 % and 900 %. Conversely, the chelating of Mn ²⁺ almost totally diminished Mn ²⁺ -enhanced lipopolysaccharide-induced gene expression. In addition, Mn ²⁺ exerted its ability to potentiate LPS-induced innate immune gene expression regardless of slight pH changes. Importantly, we found that Mn ²⁺ potentiates lipopolysaccharide-induced immune responses independent of TLR4 but partially relies on cGAS-STING pathway. Further in vivo study showed that colloidal Mn ²⁺ salt (Mn jelly [MnJ]) pretreatment exacerbated lipopolysaccharide-induced septic shock and mice death. In conclusion, we demonstrated that Mn ²⁺ 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 Mn ²⁺ and may provide a potential therapeutic target to prevent excessive immune responses.
Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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