MARCO is an IFN-restricted immunometabolic decoy LPS receptor

Intracellular sensing of lipopolysaccharide 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 macrophage decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by the metabolite itaconate and the transcription factor NRF2. In the presence of IFN, itaconate mediated NRF2 stabilization is impaired, thus inhibiting MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitized mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor and reveals an intricate immunometabolic homeostatic switch that allows for optimal immune responses and resolution of inflammation.