Critical role for the <scp>AIM</scp>2 inflammasome during acute CNS bacterial infection

Abstract

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 ( NLRP 3) inflammasome, including the adapter protein ASC (apoptosis‐associated speck‐like protein containing a caspase‐1 recruitment domain), and pro‐caspase 1. Here, we utilized NLRP 3, 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 NLRP 3 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 ( AIM 2) based on the similar disease patterns between AIM 2 and ASC KO mice. Besides IL ‐1β, other key inflammatory mediators, including IL ‐6, CXCL 1, CXCL 10, and CCL 2 were significantly reduced in the CNS of AIM 2 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 AIM 2 inflammasome as a critical molecular platform for regulating IL ‐1β release and survival during acute CNS S. aureus infection. image 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.