Manganese enhances DNA- or RNA-mediated innate immune response by inducing phosphorylation of TANK-binding kinase 1

Trace metals are essential for various physiological processes, but their roles in innate immunity have not been fully explored. Here, we found that manganese (Mn) significantly enhanced DNA-mediated IFN-α, IFN-β, and IFN-λ1 production. Microarray analysis demonstrated Mn highly upregulated 351 genes, which were involved in multiple biological functions related to innate immune response. Moreover, we found that Mn(2+) alone activates phosphorylation of TANK-binding kinase 1 (TBK1). Inhibiting ataxia telangiectasia mutated (ATM) kinase using ATM inhibitor or siRNA suppressed Mn-enhanced DNA-mediated immune response with decreasing phosphorylation of TBK-1, suggesting that ATM involves in Mn-dependent phosphorylation of TBK1. Given that TBK1 is an essential mediator in DNA- or RNA-mediated signaling pathways, we further demonstrated that Mn(2+) suppressed infection of HSV-1 (DNA virus) or Sendai virus (RNA virus) into human macrophages by enhancing antiviral immunity. Our finding highlights a beneficial role of Mn in nucleic-acid-based preventive or therapeutic reagents against infectious diseases.