Blocking GSDME-mediated pyroptosis in renal tubular epithelial cells alleviates disease activity in lupus mice.

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.

• Authors: Guihu Luo, Yi He, Fangyuan Yang, Zeqing Zhai, Jiaochan Han, Wenchao Xu, Jialin Zhang, Lili Zhuang, Yanan Zhang, Yehao Li, Rui Song, Xiaoqing Luo, Jianheng Liang, Erwei Sun
• Journal: Cell death discovery (Cell Death Discov) Vol. 8 Issue 1 Pg. 113 (Mar 12 2022) ISSN: 2058-7716 [Print] United States
• PMID: 35279675 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).