Downregulation of macrophage migration inhibitory factor attenuates NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

Abstract

Sepsis-induced AKI (acute kidney injury) is considered an inflammation-related disease with high mortality. LPS-induced (Lipopolysaccharide) TLR4-NFκB pathway activation plays an important role in sepsis-induced AKI. Pyroptosis closely associated with inflammation response includes inflammasome formation, caspase1 activation and GSDMD N-terminal fragment cleavage that leads to cell membrane rupture and cell death, which may be related to the pathogenesis of sepsis-induced AKI. MIF (Macrophage migration inhibitory factor), associated with inflammation response, has been proved as a biomarker of sepsis, and perhaps regulate pyroptosis in sepsis-induced AKI. In this study, we focus on investigating the mechanism of MIF promoting pyroptosis in sepsis-induced AKI. MIF and pyroptosis-related proteins were up-regulated in kidney tissue of mice with CLP (cecum ligation puncture) surgery and in LPS-injured human kidney-2 (HK-2) cells. NLRP3 was down-regulated following the suppression of MIF topoisomerase activity by ISO-1 in kidney tissue of CLP mice. Knockdown of MIF alleviated NLRP3 inflammasome mediated pyroptosis in LPS-injured HK-2 cells. Meanwhile, we noted that phosphorylation of p65 was down-regulated by knockdown of MIF. Up-regulation of NLRP3 in response to LPS stimulation could be reversed by JSH-23, an inhibitor of NFκB pathway, but MIF was not affected. In conclusion, up-regulation of MIF in sepsis-induced AKI shows a renal damaged effect that aggravates NLRP3 inflammasome mediated cell pyroptosis through promoting phosphorylation of p65. This study demonstrated a novel mechanism of MIF regulating NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

• Authors: Tianlong Li, Haibin Sun, Yiming Li, Lianjiu Su, Jun Jiang, Ye Liu, Nanhui Jiang, Rong Huang, Jiahao Zhang, Zhiyong Peng
• Journal: Cell death discovery (Cell Death Discov) Vol. 8 Issue 1 Pg. 61 (Feb 14 2022) ISSN: 2058-7716 [Print] United States
• PMID: 35165294 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).