Abstract
Pediatric-onset systemic lupus erythematosus arises in humans and mice lacking the endonuclease Dnase1L3. When Dnase1L3 is absent, DNA from circulating apoptotic bodies is not cleared, leading to anti-DNA antibody production. Compared to early anti-DNA and anti-chromatin responses, other autoantibody responses and general immune activation in Dnase1L3−/− mice are greatly delayed. We investigated the possibility that immune activation, specifically inflammasome activation, is regulated by Dnase1L3. Here, we report that Dnase1L3 inhibition blocked both NLR family, pyrin domain containing 3 (NLRP3) and NLRC4 inflammasome-mediated release of high-mobility group box 1 protein and IL-1β. In contrast to IL-1β release, Dnase1L3 inhibition only mildly impaired NLRP3-dependent pyroptosis, as measured by propidium iodide uptake or LDH release. Mechanistically, we found that Dnase1L3 was needed to promote apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) nuclear export and speck formation. Our results demonstrate that Dnase1L3 inhibition separates cytokine secretion from pyroptosis by targeting ASC. These findings suggest that Dnase1L3 is necessary for cytokine secretion following inflammasome activation.
Highlights
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that affects over one million people in the United States [1]
Treatment with either YVAD or FCA did not reduce TNFα levels (Figure 1B). These findings demonstrate that inhibition of Dnase1L3 does not block general cytokine release but blocks IL-1β release in primary B6 bone marrow-derived macrophages (BMDM) stimulated with NLRP3 inflammasome activators
Another potential explanation for our finding that Dnase1L3 inhibition blocked IL-1β release is that the inhibitor targets streptolysin O (SLO)-dependent cell death cells independently of inflammasome activation prior to IL-1β release [19]
Summary
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that affects over one million people in the United States [1]. The hallmarks of SLE include chronic inflammation and production of self-reactive antibodies that target nuclear antigens such as anti-double-stranded DNA (anti-dsDNA) antibodies [1, 2]. SLE usually manifests in early adulthood and is typically more common in females than in males [1, 3]. ~10–20% of SLE cases show pediatric onset, where SLE first presents in childhood, sometimes as early as 2 years of age [4, 5].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
