Critical role for the AIM2 inflammasome during acute CNS bacterial infection.
Interleukin-1β (IL-1β) is essential for eliciting protective immunity during the acute phase of Staphylococcus aureus (S. aureus) infection in the central nervous system (CNS). We previously demonstrated that microglial IL-1β production in response to live S. aureus is mediated through the Nod-like receptor protein 3 (NLRP3) inflammasome, including the adapter protein ASC (apoptosis-associated speck-like protein containing a caspase-1 recruitment domain), and pro-caspase 1. Here, we utilized NLRP3, ASC, and caspase 1/11 knockout (KO) mice to demonstrate the functional significance of inflammasome activity during CNS S. aureus infection. ASC and caspase 1/11 KO animals were exquisitely sensitive, with approximately 50% of mice succumbing to infection within 24 h. Unexpectedly, the survival of NLRP3 KO mice was similar to wild-type animals, suggesting the involvement of an alternative upstream sensor, which was later identified as absent in melanoma 2 (AIM2) based on the similar disease patterns between AIM2 and ASC KO mice. Besides IL-1β, other key inflammatory mediators, including IL-6, CXCL1, CXCL10, and CCL2 were significantly reduced in the CNS of AIM2 and ASC KO mice, implicating autocrine/paracrine actions of IL-1β, as these mediators do not require inflammasome processing for secretion. These studies demonstrate a novel role for the AIM2 inflammasome as a critical molecular platform for regulating IL-1β release and survival during acute CNS S. aureus infection.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Richa
R
Hanamsagar
Amy
A
Aldrich
Tammy
T
Kielian
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001922:Brain Abscess / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020170:Caspase 1 / Q000172:deficiency / Q000502:physiology; D020169:Caspases / Q000172:deficiency / Q000502:physiology; D053471:Caspases, Initiator; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000502:physiology; D004269:DNA, Bacterial / Q000276:immunology; D004268:DNA-Binding Proteins; D004198:Disease Susceptibility; D005260:Female; D007113:Immunity, Innate; D058847:Inflammasomes / Q000502:physiology*; D018836:Inflammation Mediators / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D018448:Models, Immunological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000172:deficiency / Q000502:physiology*; D010641:Phenotype; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism
C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
AIM2; ASC; Staphylococcus aureus; caspase 1; inflammasome; interleukin-1