Metabolic Remodeling, Inflammasome Activation, and Pyroptosis in Macrophages Stimulated by Porphyromonas gingivalis and Its Outer Membrane Vesicles

作者：Andrew J. Fleetwood, Man K.S. Lee, William Singleton, Adrian Achuthan, Ming-Chin Lee, Neil M. O’Brien‐Simpson, Andrew D. Cook, Andrew Murphy, Stuart G. Dashper, Eric C. Reynolds, John A. Hamilton · 发表于：Frontiers in Cellular and Infection Microbiology · 年份：2017 · DOI：10.3389/fcimb.2017.00351 · 被引用次数：207 · 研究领域：Oral microbiology and periodontitis research、Streptococcal Infections and Treatments、Inflammasome and immune disorders

Porphyromonas gingivalis is one of the bacterial species most closely associated with periodontitis and can shed large numbers of outer membrane vesicles (OMVs), which are increasingly thought to play a significant role in bacterial virulence and pathogenicity. Macrophages are amongst the first immune cells to respond to bacteria and their products, so we sought to directly compare the response of macrophages to P. gingivalis or its purified OMVs. Macrophages stimulated with OMVs produced large amounts of TNF, IL-12p70, IL-6, IL-10, IFN and nitric oxide compared to cells infected with P. gingivalis, which produced very low levels of these mediators. Both P. gingivalis and OMVs induced a shift in macrophage metabolism from oxidative phosphorylation (OXPHOS) to glycolysis, which was supported by enhanced lactate release, decreased mitochondrial oxygen consumption with reduced spare respiratory capacity, as well as increased mitochondrial reactive oxygen species (ROS) production. Corresponding to this metabolic shift, gene expression analysis of macrophages infected with P. gingivalis or stimulated with OMVs revealed a broad transcriptional upregulation of genes critical to glycolysis and a downregulation of genes associated with the TCA cycle. Upon examination of inflammasome signalling and pyroptosis it was found that P. gingivalis did not activate the inflammasome in macrophages as the mature forms of caspase-1, IL-1β and IL-18 were not detected and there was no extracellul...