Loss of ATF3 exacerbates liver damage through the activation of mTOR/p70S6K/ HIF-1\u03b1 signaling pathway in liver inflammatory injury

Qiang Zhu,Longfeng Jiang,Bibo Ke,Feng Zhang,Changyong Li,Han Wang,Xuehao Wang,Bin Jiang,Xuhao Ni,Ling Lu

doi:10.1038/s41419-018-0894-1

Abstract

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays important roles in regulating immune and metabolic homeostasis. Activation of the mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) transcription factors are crucial for the regulation of immune cell function. Here, we investigated the mechanism by which the ATF3/mTOR/HIF-1 axis regulates immune responses in a liver ischemia/reperfusion injury (IRI) model. Deletion of ATF3 exacerbated liver damage, as evidenced by increased levels of serum ALT, intrahepatic macrophage/neutrophil trafficking, hepatocellular apoptosis, and the upregulation of pro-inflammatory mediators. ATF3 deficiency promoted mTOR and p70S6K phosphorylation, activated high mobility group box 1 (HMGB1) and TLR4, inhibited prolyl-hydroxylase 1 (PHD1), and increased HIF-1α activity, leading to Foxp3 downregulation and RORγt and IL-17A upregulation in IRI livers. Blocking mTOR or p70S6K in ATF3 knockout (KO) mice or bone marrow-derived macrophages (BMMs) downregulated HMGB1, TLR4, and HIF-1α and upregulated PHD1, increasing Foxp3 and decreasing IL-17A levels in vitro. Silencing of HIF-1α in ATF3 KO mice ameliorated IRI-induced liver damage in parallel with the downregulation of IL-17A in ATF3-deficient mice. These findings demonstrated that ATF3 deficiency activated mTOR/p70S6K/HIF-1α signaling, which was crucial for the modulation of TLR4-driven inflammatory responses and T cell development. The present study provides potential therapeutic targets for the treatment of liver IRI followed by liver transplantation.

Highlights

Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver transplantation and resection
Having demonstrated the important role of macrophage p70S6K/hypoxia-inducible factor (HIF)-1α signaling in the modulation of innate and adaptive immunity in vitro, we investigated whether disruption of macrophage HIF-1α in Activating transcription factor 3 (ATF3) KO mice affected inflammatory responses and T cell differentiation in mouse liver IRI
The data can be summarized as follows: (i) ATF3 deficiency exacerbated IR-induced liver damage, increased macrophage/neutrophil trafficking, promoted mechanistic target of rapamycin (mTOR) and its downstream p70S6K, and activated TLR4/ NF-κB; and (ii) ATF3-mediated mTOR/p70S6K induced HIF-1α signaling, which was essential for T cell differentiation in liver IRI

Summary

Introduction

Liver ischemia and reperfusion injury (IRI) is a major problem associated with liver transplantation and resection. Liver inflammatory responses induced by IR can exacerbate liver damage. Expressing T cells played a crucial role in mediating hepatic IRI9. ATF3 can be induced by various stress signals including ischemia[10], ER stress[11], endotoxins, and cytokines[12]. ATF3 is rapidly and preferentially induced during the early stage of the inflammatory response in organ IRI, such as in the kidney[13,14] and brain[15]. Overexpression of ATF3 inhibits oxidative stress-induced apoptotic cell death in renal cells[13], whereas disruption of ATF3 increases pro-inflammatory cytokine release, leading to increased susceptibility to endotoxic shockinduced cell death[16]

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Results

Conclusion