A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome.
The mechanism by which bacterial pathogens activate caspase-1 via Nlrp3 remains poorly understood. In this study, we show that the ability of Staphylococcus aureus, a leading cause of infection in humans, to activate caspase-1 and induce IL-1beta secretion resides in culture supernatants of growing bacteria. Caspase-1 activation induced by S. aureus required alpha-, beta-, and gamma-hemolysins and the host Nlrp3 inflammasome. Mechanistically, alpha- and beta-hemolysins alone did not trigger caspase-1 activation, but they did so in the presence of bacterial lipoproteins released by S. aureus. Notably, caspase-1 activation induced by S. aureus supernatant was independent of the P2X7 receptor and the essential TLR adaptors MyD88 and TIR domain-containing adapter-inducing IFN-beta, but was inhibited by extracellular K(+). These results indicate that S. aureus hemolysins circumvent the requirement of ATP and the P2X7 receptor to induce caspase-1 activation via Nlrp3. Furthermore, these studies revealed that hemolysins promote in the presence of lipoproteins the activation of the Nlrp3 inflammasome.
Muñoz-Planillo
Raúl
R
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Franchi
Luigi
L
Miller
Lloyd S
LS
Núñez
Gabriel
G
D000255:Adenosine Triphosphate; D000818:Animals; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D006460:Hemolysin Proteins / Q000502:physiology*; D007249:Inflammation / Q000209:etiology; D053583:Interleukin-1beta / Q000378:metabolism; D008074:Lipoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000494:pharmacology; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus / Q000276:immunology*
D001426:Bacterial Proteins; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D053583:Interleukin-1beta; D008074:Lipoproteins; D046912:Multiprotein Complexes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020170:Caspase 1; D011188:Potassium