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Published on: June 8, 2022
Blocking GSDME-mediated pyroptosis in renal tubular epithelial cells alleviates disease activity in lupus mice
Guihu Luo1,2, Yi He1, Fangyuan Yang1
1The Third Affiliated Hospital of Southern Medical University, Department of Rheumatology and Immunology, Guangzhou, China.
Abstract:
An increase in apoptosis and/or defects in the clearance of apoptotic cells resulting in massive secondary necrosis have been recognized as the main causes of systemic lupus erythematosus (SLE). Recent findings have revealed that gasdermin E (GSDME)-mediated pyroptosis is a mechanism associated with secondary necrosis. We aimed to investigate the effects of GSDME-mediated pyroptosis on disease activity in lupus mice. In vivo, high levels of GSDME expression were observed in the renal tubules of pristane-induced lupus (PIL) mice and SLE patients. In lupus mice, GSDME knockout or SP600125 administration effectively ameliorated lupus-like features by inhibiting GSDME-mediated renal tubular epithelial cell pyroptosis. In vitro, treatment with tumour necrosis factor-α (TNF-α) plus cycloheximide (CHX) or SLE sera induced HK2 cells to undergo pyroptosis in a caspase-3- and GSDME-dependent manner. Likewise, SP600125 significantly reduced GSDME expression and decreased pyroptosis in HK2 cells. GSDME-mediated pyroptosis may be associated with SLE pathogenesis, and targeting GSDME may be a potential strategy for treating SLE.
Insights
Gasdermin E (GSDME)-mediated pyroptosis contributes to systemic lupus erythematosus (SLE) pathogenesis. Inhibiting GSDME pyroptosis in lupus mice ameliorated disease activity, suggesting GSDME as a potential therapeutic target for SLE.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Systemic lupus erythematosus (SLE) is linked to increased apoptosis and impaired clearance of apoptotic cells, leading to secondary necrosis.
- Recent research implicates gasdermin E (GSDME)-mediated pyroptosis in secondary necrosis.
Purpose of the Study:
- To investigate the role of GSDME-mediated pyroptosis in the disease activity of lupus.
- To explore GSDME as a potential therapeutic target for SLE.
Main Methods:
- Assessed GSDME expression in renal tubules of lupus mice and SLE patients.
- Utilized GSDME knockout and SP600125 (a GSDME inhibitor) in a lupus mouse model.
- Induced pyroptosis in HK2 cells using TNF-α/CHX or SLE sera in vitro.
- Evaluated the effects of GSDME inhibition on pyroptosis and lupus-like features.
Main Results:
- Elevated GSDME expression was found in the kidneys of lupus mice and SLE patients.
- GSDME knockout or SP600125 treatment reduced lupus-like symptoms in mice by inhibiting pyroptosis.
- In vitro studies confirmed GSDME and caspase-3 dependency in pyroptosis induction by SLE-related stimuli.
- SP600125 effectively suppressed GSDME expression and pyroptosis in kidney cells.
Conclusions:
- GSDME-mediated pyroptosis is associated with the pathogenesis of SLE.
- Targeting GSDME presents a promising therapeutic strategy for treating SLE.
