TLR-induced PAI-2 expression suppresses IL-1 beta processing via increasing autophagy and NLRP3 degradation
Resource
Proc. Natl. Acad. Sci. U. S. A., 110(40), 16079-16084
Journal
Proc. Natl. Acad. Sci. U. S. A.
Journal Volume
110
Journal Issue
40
Pages
16079-16084
Date Issued
2013
Date
2013
Author(s)
Chuang, Shih-Yi
Yang, Chih-Hsiang
Chou, Chih-Chang
Chiang, Yu-Ping
Chuang, Tsung-Hsien
Hsu, Li-Chung
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-1 beta 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-1 beta 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-1 beta 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-1 beta-driven inflammation.
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