U1-Small Nuclear Ribonucleoprotein Activates the NLRP3 Inflammasome in Human Monocytes

The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-l containing cytosolic protein complex that is essential for processing and secretion of IL-1 beta. 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-1 beta production. Reactive oxygen species and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR718 pathway decreased IL-1 beta 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. The Journal of Immunology, 20112, 188: 4769-4775.