CARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages

Interleukin-1 beta (IL-1 beta) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1 beta production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1 beta by fine-tuning pro-IL-1 beta expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity. CARD9 is suppressed during Salmonella enterica serovar Typhimurium infection, facilitating increased IL-1 beta production. CARD9 is, therefore, a central signalling hub that coordinates a pathogen-specific host inflammatory response.