Self Double-Stranded (Ds)Dna Induces Il-1B Production From Human Monocytes By Activating Nlrp3 Inflammasome In The Presence Of Anti–Dsdna Antibodies

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Self Double-Stranded (ds)DNA Induces IL-1β Production from Human Monocytes by Activating NLRP3 Inflammasome in the Presence of Anti −dsDNA Antibodies
Min Sun Shin, Youna Kang, Naeun Lee, Elizabeth R. Wahl, Sang Hyun Kim, Ki Soo Kang, Rossitza Lazova and Insoo Kang
Downloaded from http://jimmunol.org/ by Roberto Gonzalez-Amaro on February 1,2013

J Immunol published online 11 January 2013 http://www.jimmunol.org/content/early/2013/01/11/jimmun ol.1201195

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2013 by The American Association of Immunologists, Inc. All rightsreserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.

Published January 11, 2013, doi:10.4049/jimmunol.1201195
The Journal of Immunology

Self Double-Stranded (ds)DNA Induces IL-1b Production from Human Monocytes by Activating NLRP3 Inflammasome in the Presence of Anti–dsDNA Antibodies
Min Sun Shin,* Youna Kang,* Naeun Lee,* Elizabeth R. Wahl,* Sang Hyun Kim,*,† Ki Soo Kang,*,‡ RossitzaLazova,x and Insoo Kang*
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-1b 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-1b is produced primarily by innateimmune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1b production requires cleaving pro–IL-b into IL-1b by the caspase-1–associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1b production from human monocytes dependent on serum or purified IgG containing anti–dsDNA Abs by activating thenucleotide-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-1b production. Supernatants from monocytes treated with a combination of self dsDNA and anti–dsDNA Ab+ serum promoted IL-17 production from CD4+ Tcells in an IL-1b–dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1b production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K+ efflux, leading to the increased Th17 cell response. The Journal of Immunology, 2013, 190: 000–000. he innate immune cellssuch as monocytes, macrophages, and dendritic cells provide the first line of defense against microorganisms. These cells are armed with the germ line–encoded pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) commonly found in microorganisms (1, 2). Different classes of PRRs have been identified. These receptors include TLRs, retinoic acid–induciblegene-I–like receptors, nucleotide-binding oligomerization domain–like receptors (NLRs), and absent in melanoma 2 (AIM2) (1–3). TLRs that exist on the cell surface or within the intracellular vesicular compartments, such as endosomes and lysosomes, recognize PAMPs present outside of cells or delivered into these
*Department of Internal Medicine, Yale University School of Medicine, New Haven, CT...