Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria.
Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1β (IL-1β) and IL-18. Although infection with wild-type Salmonella typhimurium is lethal to mice, we show here that a strain that persistently expresses flagellin was cleared by the cytosolic flagellin-detection pathway through the activation of caspase-1 by the NLRC4 inflammasome; however, this clearance was independent of IL-1β and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1β and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.
Institute for Systems Biology, Seattle, Washington, USA. emiao@systemsbiology.org
Edward A
EA
Miao
Irina A
IA
Leaf
Piper M
PM
Treuting
Dat P
DP
Mao
Monica
M
Dors
Anasuya
A
Sarkar
Sarah E
SE
Warren
Mark D
MD
Wewers
Alan
A
Aderem
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D020170:Caspase 1