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 Specklike 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.

Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas Q61L )-driven SerpinB2 expression

“…We have not detected changes in stress-induced apoptosis in cells either lacking or overexpressing SerpinB2, or any evidence of attenuated apoptosis in DUSP5 −/− skin or papillomas. SerpinB2 has also been reported to promote autophagy and is associated with senescence (33,34). In human cancer, reports show both favorable (breast and pancreas) and poor (colorectal and ovarian) prognoses associated with high SerpinB2 levels (35).…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…[130][131][132][133] Autophagy acts as a negative regulator of NLRP3 inflammasome activation through various mechanisms, including direct inhibition of NLRP3 inflammasome activation by removing sources of endogenous NLRP3 inflammasome agonists, such as damaged mitochondria and mitochondrial DNA, 62,69,132 suppression of IL-1b secretion by targeting pro-IL-1b for lysosomal degradation, 134 and selective degradation of inflammasome components, such as NLRP3 and ASC. 131,135 More detailed information on the negative regulation of the NLRP3 inflammasome, including the roles of microRNAs and autophagy, has been detailed in recent reviews. 136 Together, efforts to identify new negative regulators of NLRP3 inflammasome activation may provide novel strategies to treat acute and chronic inflammatory diseases associated with aberrant activation of the NLRP3 inflammasome.…”

Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription

“…Among these regulators, several molecules are directly inhibiting NLRP3 protein expression to attenuate inflammasome activation, such as plasminogen activator inhibitor type 2 (ref. 18) and miR-223 (refs 19,20). Plasminogen activator inhibitor type 2 suppresses NLRP3 expression via increasing autophagy and NLRP3 degradation 18 .…”

“…18) and miR-223 (refs 19,20). Plasminogen activator inhibitor type 2 suppresses NLRP3 expression via increasing autophagy and NLRP3 degradation 18 . MiR-223 suppresses NLRP3 expression through a conserved binding site within the 3 0 untranslated region of NLRP3, translating to reduced NLRP3 inflammasome activity 19,20 .…”