Surprisingly, we show that in response to Salmonella infection CARD9 negatively regulates NLRP3-induced IL-1β production, but not pyroptosis, in murine bone marrow-derived macrophages (BMDMs) by two distinct mechanisms: (i) by fine-tuning pro-IL-1β expression; and (ii) by reducing NLRP3 activation through modulation of SYK and caspase-8 activity. The gene discussed is CARD9; the disease is Salmonella Infections.