title: TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation.
abstract: The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation 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 activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3- and ASC (apoptosis-associated Speck-like protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation 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 reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR- or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 10002, Taiwan.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Chuang
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Yang
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Chou
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Chiang
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Hsu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D015151:Immunoblotting; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017396:Plasminogen Activator Inhibitor 2; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007770:L-Lactate Dehydrogenase; D020170:Caspase 1
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