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 (SLE or lupus) is the autoimmune response against self nuclear antigens, including dsDNA. The increased expression of the pro-inflammatory cytokine IL-1β has been found in the cutaneous lesion and peripheral blood mononuclear cells from lupus patients, suggesting a potential involvement of this cytokine in the pathogenesis of lupus. IL-1β is produced primarily by innate immune cells like monocytes and can promote 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. Here we show that self dsDNA induces IL-1β production from human monocytes dependently of serum or purified IgG containing anti-dsDNA antibodies by activating the 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 antibody-positive 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.

IL-6 Receptor α Defines Effector Memory CD8+T Cells Producing Th2 Cytokines and Expanding in Asthma

“…Quantitative reverse transcriptase polymerase chain reaction and GATA3 gene knockdown were done as previously described with some modifications (see the online supplement METHODS) (22).…”

Targeting the inflammasome in rheumatic diseases

“…Ultimate assembly and activation of the inflammasome requires ligands specific for different inflammasome scaffolds or cellular metabolic changes. These “signal 2” stimuli are as diverse as bacterial peptidoglycans, crystalline materials, oxidative stress and nucleic acids (10–13). …”

“…Caspase-1 is inhibited by thalidomide, a medication used for multiple myeloma and for refractory rheumatic disease such as cutaneous lupus(21, 22). Antimalarial medications, such as hydroxychloroquine and chloroquine, which interferes with toll-like receptor (TLR) 7 and 9 activation in the lysosomal compartment, blocks inflammasome activation and IL-1β release following certain inflammasome activating triggers(13, 23). Colchicine, which inhibits microtubule assembly, is able to block inflammasome activation by preventing co-localization of ASC with NLRP3(24, 25).…”

“…Upregulation of inflammasome components has been noted in lupus nephritis biopsies(29), and overexpression of inflammasome scaffolds such as IFI16 and AIM2 have also been reported in leukocytes from SLE patients(30). Immune complexes containing DNA or RNA antigens, can prime the inflammasome for activation and subsequently trigger assembly of NLRP3 inflammasome complexes (13, 23). The activated complement component, C3a, promotes ATP secretion and thus serves as a trigger for inflammasome activation(31).…”

Dp2-Induce Autoantigen/Autoantibody Production from Patients with Systemic Lupus Erythematosus and Its Modulation by Cppecp

“…Kahlenberg, et al demonstrated an upregulation of NLRP3 and caspase-1 in lupus nephritis biopsies [8]. Furthermore, immune complexes such as complement and autoantigen/autoantibody complex have been demonstrated to induce inflammasome activation through the stimulation of TLR dependent activation of NFκB, which then causes the NLRP3 inflammasome activation [9,10]. Neutrophil extracellular traps have been recently demonstrated, and could activate caspase-1, causing IL-1β and IL-18 over expression in macrophages derived from SLE patients [11].…”