title: Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies.
abstract: The pathogenic hallmark of systemic lupus erythematosus is the autoimmune response against self nuclear Ags, including dsDNA. The increased expression of the proinflammatory cytokine IL-1β has been found in the cutaneous lesion and PBMCs from lupus patients, suggesting a potential involvement of this cytokine in the pathogenesis of lupus. IL-1β is produced primarily by innate immune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1β production requires cleaving pro-IL-β into IL-1β by the caspase-1-associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1β production from human monocytes dependent on serum or purified IgG containing anti-dsDNA Abs by activating the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Reactive oxygen species (ROS) and K(+) efflux were involved in this activation. Knocking down the NLRP3 or inhibiting caspase-1, ROS, and K(+) efflux decreased IL-1β production. Supernatants from monocytes treated with a combination of self dsDNA and anti-dsDNA Ab(+) serum promoted IL-17 production from CD4(+) T cells in an IL-1β-dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1β production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K(+) efflux, leading to the increased Th17 cell response.
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Min Sun
authors: MS
authors: Shin
authors: Youna
authors: Y
authors: Kang
authors: Naeun
authors: N
authors: Lee
authors: Elizabeth R
authors: ER
authors: Wahl
authors: Sang Hyun
authors: SH
authors: Kim
authors: Ki Soo
authors: KS
authors: Kang
authors: Rossitza
authors: R
authors: Lazova
authors: Insoo
authors: I
authors: Kang
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000502:physiology*; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D020170:Caspase 1 / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000097:blood / Q000276:immunology / Q000502:physiology*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000097:blood; D019169:Jurkat Cells; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D044967:Serum / Q000502:physiology
chemical_list: D001323:Autoantibodies; D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D004247:DNA; D020170:Caspase 1