期刊
JOURNAL OF NEUROCHEMISTRY
卷 119, 期 4, 页码 736-748出版社
WILEY
DOI: 10.1111/j.1471-4159.2011.07481.x
关键词
IL-1 beta; IL-18; inflammasome; microglia; NLRP3; P2X(7)R
资金
- NIH National Institute of Neurological Disorders and Stroke [2R01 NS055385]
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-1 beta and IL-18 processing following exposure to both pathogen-and danger-associated molecular patterns. Although previous studies from our laboratory have established that IL-1 beta 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-1 beta and IL-18 release was examined in primary microglia. Interestingly, we found that IL-1 beta, 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 a-and gamma-hemolysins produced by live bacteria. A cathepsin B inhibitor attenuated IL-beta release from NLRP3 and ASC knockout microglia, demonstrating the existence of alternative inflammasome-independent mechanisms for IL-1 beta processing. In contrast, microglial IL-18 secretion occurred independently of cathepsin B and inflammasome action. Collectively, these results demonstrate that microglial IL-1 beta processing is regulated by multiple pathways and diverges from mechanisms utilized for IL-18 cleavage. Understanding the molecular events that regulate IL-1 beta production is important for modulating this potent proinflammatory cytokine during CNS disease.
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