Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Ruyuan He,Qing Geng,Weichen Lin,Wei Wang,Wenyang Jiang,Lin Zhang,Ning Li,Bo Hao,Heng Meng,Rui Xiong,Bohao Liu,Boxin Geng

doi:10.1038/s41420-021-00807-3

Abstract

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.

Highlights

As a life‐threatening condition, sepsis is the foremost contributor to hospital death
Itaconate is the prime example of metabolic reprogramming in macrophage and is synthesized as a by-product of the Krebs cycle [22]
We demonstrated for the first time that itaconate can alleviate the sepsis-induced acute lung injury (ALI) through inhibiting ferroptosis of macrophage (Fig. 7)

Summary

Introduction

As a life‐threatening condition, sepsis is the foremost contributor to hospital death. Sepsis-induced injury, shock, and dysfunction of multiple organs remain the major cause of death in septic patients [1]. The lungs are susceptible to injury during sepsis, and the primary risk factors of acute lung injury (ALI) in >50% patients were attributed to sepsis [2]. The pathophysiology and pathogenesis of sepsis-induced ALI are not fully understood. As the most common lung immune cells at homeostasis [3], macrophage plays a crucial role in sepsis-induced ALI. The recruited and activated macrophages by lipopolysaccharide (LPS) and originally resident alveolar macrophages can release pro-inflammatory cytokines and induce neutrophil infiltration [4], further aggravating inflammation, destruction of the endothelial barrier, and blockage of pulmonary microcirculation, intensifying lung injury [5]

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