Self double-stranded (ds)DNA induces IL-1? 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-1? 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-1? is produced primarily by innate immune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1? production requires cleaving pro-IL-? into IL-1? by the caspase-1-associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1? 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-1? 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-1?-dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1? production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K(+) efflux, leading to the increased Th17 cell response.

SUBMITTER: Shin MS 

PROVIDER: S-EPMC3563755 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature