Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage

Abstract

Objective Gasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as 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), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies. Methods An imiquimod‐induced model of SLE was tested in GSDMD−/− mice (n = 30), with wild‐type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane‐induced lung injury in GSDMD−/− mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD 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 absence of GSDMD in mice with pristane‐induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti–double‐stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, 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.

Novel Effects of Combination Therapy Through Inhibition of Caspase-1/Gasdermin D Induced-Pyroptosis in Lupus Nephritis

“…In addition, the activation of caspase-8 was much enhanced in macrophages that were GSDMD deficient. Significant activation of caspase-8 was also found in TLR7-induced GSDMD-deficient LN mice (34). Thus, in the absence of GSDMD, it is likely that caspase-1 cooperates with caspase-8 to cause caspase-3-GSDME-mediated apoptosis to switch to pyroptosis in LN, a hypothesis that demands further experimental investigation.…”

Channelling inflammation: gasdermins in physiology and disease

“…For instance, GSDMD inhibition in a cell can activate the interferon response 182 . In a mouse study that modelled systemic lupus erythematosus (SLE) using injected imiquimod, the severity of SLE was unexpectedly exacerbated in Gsdmd -/mice, leading to more severe kidney and pulmonary pathology, more autoantibodies and reduced mortality 183 . Type I interferons play an important driving role in many SLE models and in patients with SLE.…”

Disulfiram alleviates pristane-induced lupus via inhibiting GSDMD-mediated pyroptosis

“…On the one hand, consistent with our findings, expression and activation of GSDMD were increased in kidney specimens of SLE patients and lupus mice, which could be inhibited by combination therapy of different immunosuppressive agents [ 26 ]. On the other hand, in a TLR7-induced model of SLE, GSDMD −/− mice developed more severe kidney damage and produced more autoantibodies [ 59 ]. The possible reason was that in the absence of GSDMD, the NLRP3 inflammasome might cooperate with caspase-3/8 to cause GSDME-induced pyroptosis [ 60 , 61 ].…”