Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance
Jingjing Tang, Xiao Wang, Shukun Chen, Tianyuan Chang, Yanchao Gu, Fuhua Zhang, Jing Hou, Yi Luo, Mengyuan Li, Jianan Huang, Mohua Liu, Lei Zhang, Yao Wang, Xihui Shen, Lei Xu
Abstract
Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD + /NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD + /NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD + /NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD + /NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD + /NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD + /NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.