Abstract
Interleukin-1β (IL-1β) 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-1β 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-1β by fine-tuning pro-IL-1β 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-1β production. CARD9 is, therefore, a central signalling hub that coordinates a pathogen-specific host inflammatory response.
Highlights
Interleukin-1b (IL-1b) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation
Non-canonical inflammasomes are formed in response to activation of other pattern recognition receptors (PRRs), such as the complex formed by dectin-1, spleen tyrosine kinase (SYK) and caspase-8 in response to fungal infection[2,3,4]
To evaluate whether CARD9 plays a role in inflammasome activity, we infected bone marrow-derived macrophages (BMDMs) from wild type (WT), Card[9] À / À and Nlrc[4] À / À C57BL/6 mice with S
Summary
Interleukin-1b (IL-1b) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. 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-1b production during bacterial infection. In response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1b by fine-tuning pro-IL-1b expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity. We show that in response to Salmonella infection CARD9 negatively regulates NLRP3-induced IL-1b production, but not pyroptosis, in murine bone marrow-derived macrophages (BMDMs) by two distinct mechanisms: (i) by fine-tuning pro-IL-1b expression; and (ii) by reducing NLRP3 activation through modulation of SYK and caspase-8 activity. We propose that CARD9 is a central signalling hub that can negatively or positively regulate proinflammatory signalling to coordinate a pathogen-specific host inflammatory response to infection
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