Non-canonical TLR signaling restricts cytosolic LPS detection.

Intracellular sensing of lipopolysaccharide (LPS) is an essential component of pathogen detection that governs the innate immune response. However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.