title: Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor.
abstract: Macrophages play a crucial role in the innate immune response against the human pathogen Streptococcus pyogenes, yet the innate immune response against the bacterium is poorly characterized. In the present study, we show that caspase-1 activation and IL-1beta secretion were induced by live, but not killed, S. pyogenes, and required expression of the pore-forming toxin streptolysin O. Using macrophages deficient in inflammasome components, we found that both NLR family pyrin domain-containing 3 (Nlrp3) and apoptosis-associated speck-like protein (Asc) were crucial for caspase-1 activation and IL-1beta secretion, but dispensable for pro-IL-1beta induction, in response to S. pyogenes infection. Conversely, macrophages deficient in the essential TLR adaptors Myd88 and Trif showed normal activation of caspase-1, but impaired induction of pro-IL-1beta and secretion of IL-1beta. Notably, activation of caspase-1 by TLR2 and TLR4 ligands in the presence of streptolysin O required Myd88/Trif, whereas that induced by S. pyogenes was blocked by inhibition of NF-kappaB. Unlike activation of the Nlrp3 inflammasome by TLR ligands, the induction of caspase-1 activation by S. pyogenes did not require exogenous ATP or the P2X7R. In vivo experiments revealed that Nlrp3 was critical for the production of IL-1beta but was not important for survival in a mouse model of S. pyogenes peritoneal infection. These results indicate that caspase-1 activation in response to S. pyogenes infection requires NF-kappaB and the virulence factor streptolysin O, but proceeds independently of P2X7R and TLR signaling.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Harder
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.forename: Raúl
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Park
authors.forename: Thornik
authors.initials: T
authors.lastname: Reimer
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D011498:Protein Precursors / Q000096:biosynthesis / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013290:Streptococcal Infections / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology*; D013301:Streptolysins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D046912:Multiprotein Complexes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D011498:Protein Precursors; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013301:Streptolysins; D051193:Toll-Like Receptors; C025964:streptolysin O; D020170:Caspase 1