U1-snRNP activates the NLRP3 inflammasome in human monocytes (171.7)

Abstract

Abstract The NLRP3 (NOD-like receptor family, pyrin domain containing 3) 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) which includes U1-small nuclear RNA (U1-snRNA) is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Antibodies against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus (SLE), 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. Here we show that U1-snRNP activates the NLRP3 inflammasome in CD14+ human monocytes dependently of anti-U1-snRNP antibodies, leading to IL-1β production. Reactive oxygen species (ROS) and K+ efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR 7/8 pathway decreased IL-1β production from monocytes treated with U1-snRNP in the presence of anti-U1-snRNP antibodies. Plus, the expression of caspase-1 and IL-1β by CD14+ cells was found in cutaneous lupus tissue. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like SLE where anti-U1-snRNP antibodies are present.