Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

Yuting Jin,Ronald W Busuttil,Mingwei Sheng,Ana J Coito,Song Wei,Jerzy W Kupiec-Weglinski,Dongwei Xu,Changyong Li,Jianjun Zhu,Andrew Zhong,Bibo Ke,Sergio Duarte,Qiang Xia

doi:10.1038/s41423-019-0318-x

Abstract

Notch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

Highlights

Hepatic ischemia/reperfusion injury (IRI) is one of the leading causes of hepatocellular dysfunction or failure during liver transplantation or resection
We demonstrate that myeloid Notch[1] signaling promotes heat shock transcription factor 1 (HSF1) and Snail activation, which in turn controls NLRP3mediated innate immunity during IR-triggered liver inflammation
JAG1-mediated myeloid Notch[1] signaling reduces hepatocellular damage in IR-stressed liver Myeloid-specific Notch1-deficient (Notch1M-KO) and Notch1proficient (Notch1FL/FL) mice treated with recombinant JAG1 or phosphate buffer saline (PBS) were subjected to liver IR (90 min)

Summary

Introduction

Hepatic ischemia/reperfusion injury (IRI) is one of the leading causes of hepatocellular dysfunction or failure during liver transplantation or resection. The Snail family of transcription factors consists of Snail[1] (Snail), Snail[2] (Slug) and Snail[3] (Smuc), which share an evolutionarily conserved role in the processes of cell development and differentiation.[3] Snail acts primarily as a key regulator of the epithelial−mesenchymal transition and contributes to cell survival.[4,5] Activation of Snail induces anti-inflammatory cytokines and modulates immune responses.[6] During tissue inflammation and injury, Snail promotes wound healing through regulation of TGF-β signaling.[7] Snail regulates cell growth via an ROS-mediated pathway. Disruption of Snail signaling was shown to increase ROS production to cause reduced cell survival under oxidative stress,[8] suggesting that Snail may play an important role in the modulation of ROS-mediated inflammation

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Results

Conclusion