Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens.
Enteric pathogens represent a major cause of morbidity and mortality worldwide. Toll-like receptor (TLR) and inflammasome signaling are critical for host responses against these pathogens, but how these pathways are integrated remains unclear. Here, we show that TLR4 and the TLR adaptor TRIF are required for inflammasome activation in macrophages infected with the enteric pathogens Escherichia coli and Citrobacter rodentium. In contrast, TLR4 and TRIF were dispensable for Salmonella typhimurium-induced caspase-1 activation. TRIF regulated expression of caspase-11, a caspase-1-related protease that is critical for E. coli- and C. rodentium-induced inflammasome activation, but dispensable for inflammasome activation by S. typhimurium. Thus, TLR4- and TRIF-induced caspase-11 synthesis is critical for noncanonical Nlrp3 inflammasome activation in macrophages infected with enteric pathogens.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Prajwal
P
Gurung
R K Subbarao
RK
Malireddi
Paras K
PK
Anand
Dieter
D
Demon
Lieselotte
L
Vande Walle
Zhiping
Z
Liu
Peter
P
Vogel
Mohamed
M
Lamkanfi
Thirumala-Devi
TD
Kanneganti
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D004755:Enterobacteriaceae / Q000235:genetics / Q000276:immunology*; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D020169:Caspases; D053471:Caspases, Initiator; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051197:Toll-Like Receptor 4; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C101136:Casp4 protein, mouse