TLR-induced PAI-2 expression suppresses IL-1β processing èia increasing autophagy and NLRP3 degradation
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
110
Journal Issue
40
Pages
16079-16084
Date Issued
2013-10-01
Author(s)
Abstract
The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 acti?ation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome acti?ity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen acti?ator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain) dependent caspase-1 acti?ation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reacti?e oxygen species, NLRP3 protein le?el, and pro-IL-1β processing. Likewise, o?erexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 acti?ation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome acti?ation and re?eal a cell-autonomous mechanism which in?ersely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidati?e stress, and IL-1β-dri?en inflammation.
SDGs
Other Subjects
beclin 1; cryopyrin; inflammasome; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; lipopolysaccharide; plasminogen activator inhibitor 2; reactive oxygen metabolite; toll like receptor; toll like receptor 2; toll like receptor 4; animal cell; apoptosis; article; autophagy; carboxy terminal sequence; cell death; controlled study; cytokine production; cytokine release; disorders of mitochondrial functions; enzyme activation; Escherichia coli; gene overexpression; human; human cell; inflammation; macrophage; mitochondrion; mouse; nonhuman; oxidative stress; priority journal; protein degradation; protein depletion; protein domain; protein expression; protein stability; signal transduction; Animals; Autophagy; Carrier Proteins; Caspase 1; Cytokines; Cytoskeletal Proteins; DNA Primers; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Gene Silencing; Immunoblotting; Inflammasomes; Interleukin-1beta; L-Lactate Dehydrogenase; Macrophages; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 2; Proteolysis; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 2; Toll-Like Receptor 4
Type
journal article