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

  • Cell Death Discov. 2022 Feb 14;8(1):61. doi: 10.1038/s41420-022-00859-z.
Tianlong Li  1 ,  Haibin Sun  1 ,  Yiming Li  1 ,  Lianjiu Su  1 ,  Jun Jiang  1 ,  Ye Liu  1 ,  Nanhui Jiang  1 ,  Rong Huang  1 ,  Jiahao Zhang  1 ,  Zhiyong Peng  2  3
Affiliations
  • 1. Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei province, 430071, China.
  • 2. Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei province, 430071, China. [email protected].
  • 3. Center of Critical Nephrology, Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15223, USA. [email protected].
PMID: 35165294 DOI: 10.1038/s41420-022-00859-z
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.

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