Background/Purpose: 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 would play a pathogenic role by promoting inflammatory cell death leading to increased generation of nuclear autoantigens and autoantibodies.

Methods: Methods: The imiquimod-induced model of SLE was tested in Gsdmd-/- and wild-type C57BL/6 (WT) mice. At euthanasia, mice were examined for serum autoantibodies, renal function, immune complex deposition, organ inflammation, immune dysregulation and type I Interferon responses. A pristane-induced lung injury model in Gsdmd-/- and WT C57BL/6 was used to further 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 TLR-7 agonists. Pulmonary involvement was also more severe in the short-term pristane model in the absence of GSDMD. Lack of GSDMD was associated with increased levels of circulating nuclear autoantigens, tissue immune complex deposition, significant expansion of myeloid cell subsets, and enhanced B cell activation and differentiation. In the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo.

Conclusion: GSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury, and may play previously unappreciated protective roles in systemic autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gasdermin-d-modulates-murine-lupus-and-its-associated-organ-damage/