Cell-Cell Propagation of NF-κB Transcription Factor and MAP Kinase Activation Amplifies Innate Immunity against Bacterial Infection

The enteroinvasive bacterium Shigella flexneri uses multiple secreted effector proteins to downregulate interleukin-8 (IL-8) expression in infected epithelial cells. Yet, massive IL-8 secretion is observed in Shigellosis. Here we report a host mechanism of cell-cell communication that circumvents the effector proteins and strongly amplifies IL-8 expression during bacterial infection. By monitoring proinflammatory signals at the single-cell level, we found that the activation of the transcription factor NF-κB and the MAP kinases JNK, ERK, and p38 rapidly propagated from infected to uninfected adjacent cells, leading to IL-8 production by uninfected bystander cells. Bystander IL-8 production was also observed during Listeria monocytogenes and Salmonella typhimurium infection. This response could be triggered by recognition of peptidoglycan and is mediated by gap junctions. Thus, we have identified a mechanism of cell-cell communication that amplifies innate immunity against bacterial infection by rapidly spreading proinflammatory signals via gap junctions to yet uninfected cells. [Display omitted] ► Inflammatory signals propagate from infected to uninfected bystander cells ► NF-κB and MAP kinases are activated in uninfected bystander cells ► Uninfected bystander cells produce IL-8 during bacterial infection ► The propagation of proinflammatory signals is mediated through gap junctions