Salmonella sensitizes macrophages for context-dependent anti-inflammatory responses

ABSTRACT Macrophages’ critical role in the innate immune response depends on their ability to change their activation state in response to environmental signals, generating cells with diverse functions ranging from antimicrobial activity to tissue repair. However, this plasticity in activation state represents a vulnerability that intracellular pathogens have evolved to exploit. Salmonella Typhimurium (STm) harnesses macrophage plasticity to promote anti-inflammatory states conducive to bacterial survival and replication. Although this anti-inflammatory state is well-characterized, how it is established remains unclear. Using smFISH, we find that STm is a weak pro-inflammatory trigger and fails to directly induce anti-inflammatory polarization. Instead, we show that STm creates a sensitized cell state with enhanced responsiveness to the cytokine IL-4. While we found that IL-4Rɑ upregulation is a common feature of infected cells, the sensitized state is independent of receptor upregulation. Polarization resulting from this sensitized state is context-dependent, with bacterial load and effector secretion distinctly amplifying expression of the anti-inflammatory genes, Il4ra and Arg1 . Together, our results establish a two-signal model in which pathogen-driven sensitization and environmental IL-4 combine to drive macrophage anti-inflammatory polarization.