PMID- 36591278 OWN - NLM STAT- MEDLINE DCOM- 20230111 LR - 20230117 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - cGAS deficiency enhances inflammasome activation in macrophages and inflammatory pathology in pristane-induced lupus. PG - 1010764 LID - 10.3389/fimmu.2022.1010764 [doi] LID - 1010764 AB - INTRODUCTION: Type I interferon (IFN) plays a vital role in the pathogenesis of systemic lupus erythematosus. Cyclic GMP AMP synthase (cGAS) is a cytosolic DNA sensor that recognizes dsDNA and creates cGAMP to activate STING-mediated type I IFN production. The activation of STING induces lupus disease in Fcgr2b deficient mice through the differentiation of dendritic cells. In contrast, Cgas-deficient mice could be generated more autoantibody production and proteinuria in pristane-induced lupus (PIL). These data suggested that the other dsDNA sensors could be involved in lupus development mechanisms. METHODS: This study aimed to identify the cGAS-mediated mechanisms contributing to lupus pathogenesis in PIL. The Cgas-deficient and WT mice were induced lupus disease with pristane and subsequently analyzed autoantibody, histopathology, and immunophenotypes. The lung tissues were analyzed with the expression profiles by RT-PCR and western blot. The bone marrow-derived macrophages were stimulated with inflammasome activators and observed pyroptosis. RESULTS: The Cgas-/- mice developed more severe pulmonary hemorrhage and autoantibody production than WT mice. The activated dendritic cells, IFN-g-, and IL-17a-producing T helper cells, and infiltrated macrophages in the lung were detected in Cgas-/- mice higher than in WT mice. We observed an increase in expression of Aim2, Casp11, and Ifi16 in the lung and serum IL-1a but IL-1b in pristane-injected Cgas-/- mice. The rise of Caspase-11 in the lung of pristane-injected Cgas-/- mice suggested noncanonical inflammasome activation. The activation of AIM2 and NLRP3 inflammasomes in bone marrow-derived macrophages (BMDMs) enhanced the number of dead cells in Cgas-/- mice compared with WT mice. Activation of the inflammasome significantly induced pyroptosis in Cgas-/- BMDMs. The dsDNA level, but not mitochondrial DNA, increased dramatically in pristane-injected Cgas-/- mice suggesting the dsDNA could be a ligand activating inflammasomes. The cGAS agonist-induced BMDM activation in the Cgas-/- mice indicated that the activation of DNA sensors other than cGAS enhanced activated macrophages. CONCLUSION: These findings suggested that cGAS hampers the unusual noncanonical inflammasome activation through other DNA sensors. CI - Copyright (c) 2022 Kumpunya, Thim-uam, Thumarat, Leelahavanichkul, Kalpongnukul, Chantaravisoot, Pisitkun and Pisitkun. FAU - Kumpunya, Sarinya AU - Kumpunya S AD - Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, Thailand. FAU - Thim-Uam, Arthid AU - Thim-Uam A AD - Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao, Thailand. FAU - Thumarat, Chisanu AU - Thumarat C AD - Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. FAU - Leelahavanichkul, Asada AU - Leelahavanichkul A AD - Center of Excellence in Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. FAU - Kalpongnukul, Nuttiya AU - Kalpongnukul N AD - Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, Thailand. AD - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. FAU - Chantaravisoot, Naphat AU - Chantaravisoot N AD - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. AD - Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. FAU - Pisitkun, Trairak AU - Pisitkun T AD - Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. AD - Epithelial Systems Biology Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States. FAU - Pisitkun, Prapaporn AU - Pisitkun P AD - Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. AD - Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221216 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Autoantibodies) RN - EC 2.7.7.- (cGAS protein, mouse) RN - 9007-49-2 (DNA) RN - 0 (Inflammasomes) RN - EC 2.7.7.- (Nucleotidyltransferases) RN - 26HZV48DT1 (pristane) SB - IM MH - Animals MH - Mice MH - Autoantibodies/genetics/immunology MH - Disease Models, Animal MH - DNA/genetics/immunology MH - *Inflammasomes/genetics/immunology MH - *Inflammation/genetics/immunology MH - *Lupus Erythematosus, Systemic/chemically induced/genetics/immunology MH - *Macrophages/immunology MH - *Nucleotidyltransferases/deficiency/genetics/immunology PMC - PMC9800982 OTO - NOTNLM OT - STING OT - autoimmune OT - cGAS OT - dsDNA OT - inflammasomes OT - lupus OT - macrophages OT - non-canonical COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/01/03 06:00 MHDA- 2023/01/04 06:00 PMCR- 2022/01/01 CRDT- 2023/01/02 04:49 PHST- 2022/08/03 00:00 [received] PHST- 2022/11/29 00:00 [accepted] PHST- 2023/01/02 04:49 [entrez] PHST- 2023/01/03 06:00 [pubmed] PHST- 2023/01/04 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.1010764 [doi] PST - epublish SO - Front Immunol. 2022 Dec 16;13:1010764. doi: 10.3389/fimmu.2022.1010764. eCollection 2022.