U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes

J Immunol. 2012 May 15;188(10):4769-75. doi: 10.4049/jimmunol.1103355. Epub 2012 Apr 6.

Abstract

The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-1-containing cytosolic protein complex that is essential for processing and secretion of IL-1β. The U1-small nuclear ribonucleoprotein (U1-snRNP) that includes U1-small nuclear RNA is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Abs against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus, suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. In this study, we show that U1-snRNP activates the NLRP3 inflammasome in CD14(+) human monocytes dependently of anti-U1-snRNP Abs, leading to IL-1β production. Reactive oxygen species and K(+) efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti-U1-snRNP Abs. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like systemic lupus erythematosus where anti-U1-snRNP Abs are present.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Antibodies / physiology
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology
  • Humans
  • Interleukin-1beta / biosynthesis
  • Lipopolysaccharide Receptors / biosynthesis
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Monocytes / immunology*
  • Monocytes / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species / metabolism
  • Ribonucleoprotein, U1 Small Nuclear / immunology
  • Ribonucleoprotein, U1 Small Nuclear / physiology*

Substances

  • Antibodies
  • Carrier Proteins
  • IL1B protein, human
  • Interleukin-1beta
  • Lipopolysaccharide Receptors
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • Ribonucleoprotein, U1 Small Nuclear