TY - JOUR
T1 - Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion
AU - Shi, Guilan
AU - Abbott, Kennady
AU - Wu, Wenbo
AU - Salter, Russell
AU - Keyel, Peter
N1 - Funding Information:
We thank Richard Flavell, Timothy Billiar, and Lisa Borghesi for generous gifts of mouse bone marrow and Chenqun Sun for the IL-1β plasmid. We thank the Center for Biologic Imaging (Pittsburgh, PA, USA) and the College of Arts & Sciences Microscopy (Lubbock, TX, USA) for use of facilities. This work was funded by NIH grants supporting RS (AI072083 and CA073743) and PK (T32CA82084), American Heart Association grant to PK (16SDG302000016SDG), Texas Tech University Center for Active Learning and Undergraduate Engagement Undergraduate Project Funding Award to KA, Texas Tech University Center for the Integration of STEM Education and Research Service Scholar Award to KA, and start-up funding from Texas Tech University to PK. The funders had no role in experimental design, analysis, and interpretation of data; preparation of the manuscript; nor in the decision to submit the article for publication.
Publisher Copyright:
© 2017 Shi, Abbott, Wu, Salter and Keyel.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - 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.
AB - 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.
M3 - Article
SP - 522
JO - Frontiers in Immunology
JF - Frontiers in Immunology
ER -