Salmonella Typhimurium Co-Opts the Host Type I IFN System To Restrict Macrophage Innate Immune Transcriptional Responses Selectively

摘要

Innate immune inflammatory responses are subject to complex layers of negative regulation at intestinal mucosal surfaces. Although the type I IFN system is critical for amplifying antiviral immunity, it has been shown to play a homeostatic role in some models of autoimmune inflammation. Type I IFN is triggered in the gut by select bacterial pathogens, but whether and how the type I IFN might regulate innate immunity in the intestinal environment have not been investigated in the context of Salmonella enterica serovar Typhimurium ( S T). S T infection of human or murine macrophages reveals that IFN-β selectively restricts the transcriptional responses mediated by both the TLRs and the NOD-like receptors. Specifically, IFN-β potently represses S T-dependent innate induction of IL-1 family cytokines and neutrophil chemokines. This IFN-β–mediated transcriptional repression was independent of the effects of IFN-β on S T - induced macrophage cell death, but significantly dependent on IL-10 regulation. We further evaluated S T pathogenesis in vivo following oral inoculation of mice lacking IFN-β. We show that IFN-β?/? mice exhibit greater resistance to oral S T infection and a slower spread of S T to distal sterile sites. This work provides mechanistic insight into the relationship between S T and type I IFN, and demonstrates an additional mechanism by which IFN-β may promote spread of enteric pathogens. This article is featured in In This Issue , p.[1907][1] [1]: /lookup/volpage/195/1907