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OBJECTIVE: Gasdermin D (GSDMD) is the key executioner of the inflammatory cell death mechanism pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), we hypothesized that GSDMD plays pathogenic roles by promoting inflammatory cell death leading to increased generation of nuclear autoantigens and autoantibodies. METHODS: The imiquimod-induced model of SLE was tested in Gsdmd(−/−) (n=30) and wild-type (WT; n=34) C57BL/6 mice. At euthanasia, mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation and type I Interferon responses. A pristane-induced lung injury model in Gsdmd(−/−) (n=7) and WT (n=10) mice was used to confirm pulmonary phenotype. Regulation of various mechanisms of cell death was investigated in the mice. RESULTS: Unexpectedly, Gsdmd(−/−) mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the pristane model in the absence of GSDMD. Lack of GSDMD was associated with increased circulating nuclear autoantigens (p |
