Critical role for the AIM2 inflammasome during acute CNS bacterial infection
Article first published online: 19 FEB 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 4, pages 704–711, May 2014
How to Cite
J. Neurochem. (2014) 129, 704–711.
- Issue published online: 23 APR 2014
- Article first published online: 19 FEB 2014
- Accepted manuscript online: 31 JAN 2014 09:03PM EST
- Manuscript Accepted: 27 JAN 2014
- Manuscript Revised: 26 DEC 2013
- Manuscript Received: 5 NOV 2013
- NIH National Institute of Neurological Disorders and Stroke. Grant Number: 2R01 NS040730
- NIAID. Grant Number: P01 AI083211
- ASC ;
- caspase 1;
- Staphylococcus aureus
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.
The AIM2 inflammasome is protective during acute CNS bacterial infection. A disconnect in phenotypes between the inflammasome sensor Nod-like receptor protein 3 (NLRP3) and its adaptor ASC (apoptosis-associated speck-like protein containing a caspase-1 recruitment domain) during acute CNS Staphylococcus aureus (S. aureus) infection led to the discovery of absent in melanoma 2 (AIM2) as a critical inflammasome sensor. The AIM2 inflammasome is potentially triggered by dsDNA in cells harboring intracellular S. aureus, leading to ASC and caspase 1 recruitment, resulting in pro-IL-1β processing and cytokine secretion. This cascade, in turn, is protective to the host during acute infection. The NLRP3 inflammasome is also activated in response to S. aureus challenge by α-hemolysin (hla); however, it is not critical for host survival. ASC also regulates the production of other inflammatory mediators, presumably via indirect effects mediated by IL-1β action.