Selective inhibition of the NLRP3 inflammasome by targeting to promyelocytic leukemia protein in mouse and human

Blood. 2013 Apr 18;121(16):3185-94. doi: 10.1182/blood-2012-05-432104. Epub 2013 Feb 21.

Abstract

The functional activities of the tumor suppressor promyelocytic leukemia protein (PML) are mostly associated with its nuclear location. In the present study, we discovered an unexpected role of PML in NLRP3 inflammasome activation. In PML-deficient macrophages, the production of IL-1β was strongly impaired. The expression of pro-IL-1β, NLRP3, ASC, and procaspase-1 was not affected in Pml(-/-) macrophages. PML deficiency selectively reduced the processing of procaspase-1. We further showed that PML is required for the assembly of the NLRP3 inflammasome in reconstitution experiment. All PML isoforms were capable of stimulating NLRP3 inflammasome activation. In Pml(-/-) macrophages, the generation of reactive oxygen species and release of mitochondrial DNA were decreased. The involvement of PML in inflammasome activation constitutes an important activity of PML and reveals a new mechanism underlying the inflammasome activation. In addition, downregulation of PML by arsenic trioxide suppressed monosodium urate (MSU)-induced IL-1β production, suggesting that targeting to PML could be used to treat NLRP3 inflammasome-associated diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Caspase 1 / immunology
  • Cell Line
  • Cells, Cultured
  • DNA, Mitochondrial / immunology
  • Down-Regulation / drug effects
  • Gene Deletion
  • Growth Inhibitors / pharmacology
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-1beta / immunology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Oxides / pharmacology
  • Promyelocytic Leukemia Protein
  • Reactive Oxygen Species / immunology
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / immunology*

Substances

  • Arsenicals
  • Carrier Proteins
  • DNA, Mitochondrial
  • Growth Inhibitors
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Nuclear Proteins
  • Oxides
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Reactive Oxygen Species
  • Transcription Factors
  • Tumor Suppressor Proteins
  • PML protein, human
  • Caspase 1
  • Arsenic Trioxide