title: Hyperactivation of the NLRP3 Inflammasome in Myeloid Cells Leads to Severe Organ Damage in Experimental Lupus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune syndrome associated with severe organ damage resulting from the activation of immune cells. Recently, a role for caspase-1 in murine lupus was described, indicating an involvement of inflammasomes in the development of SLE. Among multiple inflammasomes identified, the NLRP3 inflammasome was connected to diverse diseases, including autoimmune encephalomyelitis. However, the function of NLRP3 in SLE development remains elusive. In this study, we explored the role of NLRP3 in the development of SLE using the pristane-induced experimental lupus model. It was discovered that more severe lupus-like syndrome developed in Nlrp3-R258Wmice carrying the gain-of-function mutation. Nlrp3-R258Wmutant mice exhibited significantly higher mortality upon pristane challenge. Moreover, prominent hypercellularity and interstitial nephritis were evident in the glomeruli of Nlrp3-R258Wmice. In addition, hyperactivation of the NLRP3 inflammasome in this mouse line resulted in proteinuria and mesangial destruction. Importantly, all of these phenotypes were largely attributed to the Nlrp3-R258Wmutation expressed in myeloid cells, because Cre recombinase-mediated depletion of this mutant from such cells rescued mice from experimental lupus. Taken together, our study demonstrates a critical role for NLRP3 in the development of SLE and suggests that modulating the inflammasome signal may help to control the inflammatory damage in autoimmune diseases, including lupus.
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Lu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.|College of Life Science, Shandong Normal University, Jinan 250014, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Niu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Wu
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Xue
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yao
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Laboratory Medicine, Central Hospital of Zhabei District, Shanghai 200070, China; and.
authors.forename: Nianhong
authors.initials: N
authors.lastname: Wan
authors.affiliation: Department of Dermatology, First Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China.
authors.forename: Paride
authors.initials: P
authors.lastname: Abliz
authors.affiliation: College of Life Science, Shandong Normal University, Jinan 250014, China.
authors.forename: Guiwen
authors.initials: G
authors.lastname: Yang
authors.affiliation: College of Life Science, Shandong Normal University, Jinan 250014, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: An
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; gxmeng@ips.ac.cn.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Meng
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D015551:Autoimmunity; D018925:Chemokines / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D005921:Glomerulonephritis / Q000209:etiology; D018836:Inflammation Mediators / Q000502:physiology; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D009395:Nephritis, Interstitial / Q000209:etiology; D013729:Terpenes / Q000633:toxicity
chemical_list: D000936:Antigen-Antibody Complex; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013729:Terpenes; C009042:pristane