title: U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes.
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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Shin
authors.forename: Youna
authors.initials: Y
authors.lastname: Kang
authors.forename: Naeun
authors.initials: N
authors.lastname: Lee
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Ki Soo
authors.initials: KS
authors.lastname: Kang
authors.forename: Rossitza
authors.initials: R
authors.lastname: Lazova
authors.forename: Insoo
authors.initials: I
authors.lastname: Kang
mesh_terms: D000328:Adult; D000906:Antibodies / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D017412:Ribonucleoprotein, U1 Small Nuclear