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

Tianlong Li,Haibin Sun,Zhiyong Peng,Rong Huang,Lianjiu Su,Ye Liu,Jun Jiang,Yiming Li,Nanhui Jiang,Jiahao Zhang

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.

Highlights

IntroductionSepsis-induced AKI (acute kidney injury) is a high mortality disease related to systemic inflammation reaction [1]
Sepsis-induced AKI is a high mortality disease related to systemic inflammation reaction [1]
Renal tubular epithelial cell morphology was observed under Transmission electron microscope (TEM), in which cell pyroptosis was found

Summary

Introduction

Sepsis-induced AKI (acute kidney injury) is a high mortality disease related to systemic inflammation reaction [1]. PAMPs (Pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns) are recognized as the dominant causes of sepsis-induced AKI. PRRs (pattern recognition receptors) interact with antigens from PAMPs or DAMPs, recognized rapidly these factors [2]. TLRs (Toll-like receptors) family, especially TLR4, is a most important receptor in sepsisinduced AKI that exists extensively on the cell membrane of renal tubular epithelial cells [3]. Exposed to ligands like LPS (lipopolysaccharide), TLR4-Myd mediated phosphorylation of IRAK4 (interleukin-1-receptor-associated kinase) recruits TRAF6 (TNFreceptor-associated factor 6) interacting with TAK1 complex leading to MAPK (mitogen-activated protein kinase) and NF-κB pathway activation. NF-κB activation enhances transcription and release of cytokines like TNF-α and IL1β causing severe inflammation [4]. Kidney injury happens involving renal function and morphological change

Methods

Results

Conclusion