TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation
Date Issued
2013
Date
2013
Author(s)
Chuang, Shih-Yi
Abstract
The NLRP3 inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen- and damage-associated molecules. Dyregulation of the 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-dependent caspase-1 activation and IL-1β secretion in macrophages upon TLR2 and TLR4 engagement. TLR2 or 4 agonists induced PAI-2 expression, which subsequently stabilized autophagic protein Beclin 1 to promote autophagy resulting in decreased mitochondrial reactive oxygen species (mROS), NLRP3 protein as well as pro-IL-1β processing. Together, our data identify a new tier of TLR signaling in controlling NLRP3 inflammasome activation, and reveal a novel cell-autonomous mechanism which inversely regulates TLRs- or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.
Subjects
第二型纖溶酶原激活物抑制酶
自噬作用
介白素-1β
Type
thesis
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