Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway

Gang Liu; Yaxian Wu; Sihao Jin; Jiaojiao Sun; Bin-Bin Wan; Jiru Zhang; Yingying Wang; Zhi-Qi Gao; Dan Chen; Shengpeng Li; Qingfeng Pang; Zhiqiang Wang

doi:10.21037/atm-21-1448

Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway

Ann Transl Med. 2021 Apr;9(8):712. doi: 10.21037/atm-21-1448.

Authors

Gang Liu^{1

2}, Yaxian Wu^{2

3}, Sihao Jin^{1

2}, Jiaojiao Sun^{1

2}, Bin-Bin Wan², Jiru Zhang⁴, Yingying Wang², Zhi-Qi Gao², Dan Chen², Shengpeng Li², Qingfeng Pang², Zhiqiang Wang¹

Affiliations

¹ Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
² Wuxi School of Medicine, Jiangnan University, Wuxi, China.
³ Food Science and Technology, Jiangnan University, Wuxi, China.
⁴ Department of Anesthesiology, Affiliated Hospital of Jiangnan University, Wuxi, China.

Abstract

Background: Methicillin-resistant Staphylococcus aureus (MRSA) are a critical predisposing factor of sepsis in the clinic. As a product of human energy metabolism and immune response, itaconate can effectively reduce inflammation in the body. This research employed 4-octyl itaconate (4-OI) to illustrate that itaconate exerted anti-inflammatory effects to protect the body from acute lung injury (ALI) induced by MRSA.

Methods: HE staining and immunohistochemistry are used to evaluate the MRSA-induced ALI in mice. WB and qPCR were used to verify the effect of 4-OI on inflammation and oxidative stress caused by MRSA. Molecular docking was used to verify the binding sites of 4-OI and Keap1.

Results: We demonstrated that 4-OI treatment increased the survival ratio, attenuated the pathological damage, inhibited neutrophil infiltration, and reduced lung bacterial burden in the mouse MRSA pneumonia model. 4-OI decreased the expression of inflammatory factors by stimulating the Nrf2 in vivo and in vitro. Furthermore, 4-OI exerted its effect by promoting nuclear transport of Nrf2 in vitro. The results of molecular docking indicated that 4-OI bound to the pocket of Keap1 and exerted a stable interaction. Both Nrf2 inhibitors (ML385) and Nrf2^-/- mice abolished the protective effect of 4-OI on MRSA-induced inflammation both in vitro and in vivo.

Conclusions: 4-OI prevents lung damage caused by MRSA bacteremia via activating Nrf2/ARE pathway.

Keywords: Methicillin-resistant Staphylococcus aureus (MRSA); NF-E2-related factor 2; acute lung injury (ALI); itaconate; sepsis.