Inflammasome activation and IL‐1β/IL‐18 processing are influenced by distinct pathways in microglia

Abstract

J. Neurochem. (2011) 119 , 736–748. Abstract Microglia are important innate immune effectors against invading CNS pathogens, such as Staphylococcus aureus (S. aureus ), a common etiological agent of brain abscesses typified by widespread inflammation and necrosis. The NLRP3 inflammasome is a protein complex involved in IL‐1β and IL‐18 processing following exposure to both pathogen‐ and danger‐associated molecular patterns. Although previous studies from our laboratory have established that IL‐1β is a major cytokine product of S. aureus‐activated microglia and is pivotal for eliciting protective anti‐bacterial immunity during brain abscess development, the molecular machinery responsible for cytokine release remains to be determined. Therefore, the functional role of the NLRP3 inflammasome and its adaptor protein apoptosis‐associated speck‐like protein (ASC) in eliciting IL‐1β and IL‐18 release was examined in primary microglia. Interestingly, we found that IL‐1β, but not IL‐18 production, was significantly attenuated in both NLRP3 and ASC knockout microglia following exposure to live S. aureus . NLRP3 inflammasome activation was partially dependent on autocrine/paracrine ATP release and α‐ and γ‐hemolysins produced by live bacteria. A cathepsin B inhibitor attenuated IL‐β release from NLRP3 and ASC knockout microglia, demonstrating the existence of alternative inflammasome‐independent mechanisms for IL‐1β processing. In contrast, microglial IL‐18 secretion occurred independently of cathepsin B and inflammasome action. Collectively, these results demonstrate that microglial IL‐1β processing is regulated by multiple pathways and diverges from mechanisms utilized for IL‐18 cleavage. Understanding the molecular events that regulate IL‐1β production is important for modulating this potent proinflammatory cytokine during CNS disease.