Abstract
Nucleotide-binding oligomerization domain-like receptors (NLRs) detect pathogens and danger-associated signals within the cell. Salmonella enterica serovar Typhimurium, an intracellular pathogen, activates caspase-1 required for the processing of the proinflammatory cytokines, pro-IL-1β and pro-IL-18, and pyroptosis. In this study, we show that Salmonella infection induces the formation of an apoptosis-associated specklike protein containing a CARD (ASC)-Caspase-8-Caspase-1 inflammasome in macrophages. Caspase-8 and caspase-1 are recruited to the ASC focus independently of one other. Salmonella infection initiates caspase-8 proteolysis in a manner dependent on NLRC4 and ASC, but not NLRP3, caspase-1 or caspase-11. Caspase-8 primarily mediates the synthesis of pro-IL-1β, but is dispensable for Salmonella-induced cell death. Overall, our findings highlight that the ASC inflammasome can recruit different members of the caspase family to induce distinct effector functions in response to Salmonella infection.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Apoptosis / immunology
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism*
-
Bone Marrow Cells
-
CARD Signaling Adaptor Proteins
-
Calcium-Binding Proteins / genetics
-
Calcium-Binding Proteins / metabolism*
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism
-
Caspase 1 / genetics
-
Caspase 1 / metabolism
-
Caspase 8 / genetics
-
Caspase 8 / metabolism*
-
Caspases
-
Caspases, Initiator
-
Cells, Cultured
-
Cytoskeletal Proteins / biosynthesis
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / metabolism*
-
Inflammasomes / immunology
-
Interleukin-1beta / biosynthesis*
-
Macrophages / immunology
-
Macrophages / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
-
Salmonella Infections / immunology*
-
Salmonella Infections / metabolism
-
Salmonella typhimurium / immunology
-
Signal Transduction
Substances
-
Apoptosis Regulatory Proteins
-
CARD Signaling Adaptor Proteins
-
Calcium-Binding Proteins
-
Carrier Proteins
-
Cytoskeletal Proteins
-
Inflammasomes
-
Interleukin-1beta
-
Ipaf protein, mouse
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nlrp3 protein, mouse
-
Pycard protein, mouse
-
Receptor-Interacting Protein Serine-Threonine Kinases
-
Ripk3 protein, mouse
-
Casp4 protein, mouse
-
Caspase 8
-
Caspases
-
Caspases, Initiator
-
Caspase 1