Critical role for the AIM2 inflammasome during acute CNS bacterial infection.

Abstract

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.

• Authors: Richa Hanamsagar, Amy Aldrich, Tammy Kielian
• Journal: Journal of neurochemistry (J Neurochem) Vol. 129 Issue 4 Pg. 704-11 (May 2014) ISSN: 1471-4159 [Electronic] England
• PMID: 24484406 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 International Society for Neurochemistry.

Chemical References

• Aim2 protein, mouse
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytokines
• Cytoskeletal Proteins
• DNA, Bacterial
• DNA-Binding Proteins
• Inflammasomes
• Inflammation Mediators
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nuclear Proteins
• Pycard protein, mouse
• Casp4 protein, mouse
• Caspases
• Caspases, Initiator
• Caspase 1

Topics

• Animals
• Apoptosis Regulatory Proteins
• Brain Abscess (immunology, metabolism, microbiology)
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics, physiology)
• Caspase 1 (deficiency, physiology)
• Caspases (deficiency, physiology)
• Caspases, Initiator
• Cytokines (metabolism)
• Cytoskeletal Proteins (deficiency, physiology)
• DNA, Bacterial (immunology)
• DNA-Binding Proteins
• Disease Susceptibility
• Female
• Immunity, Innate
• Inflammasomes (physiology)
• Inflammation Mediators (physiology)
• Interleukin-1beta (metabolism)
• Male
• Methicillin-Resistant Staphylococcus aureus (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (metabolism)
• Models, Immunological
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nuclear Proteins (deficiency, physiology)
• Phenotype
• Staphylococcal Infections (immunology, metabolism)