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.
Gang Liu  1  2 ,  Yaxian Wu  2  3 ,  Sihao Jin  1  2 ,  Jiaojiao Sun  1  2 ,  Bin-Bin Wan  2 ,  Jiru Zhang  4 ,  Yingying Wang  2 ,  Zhi-Qi Gao  2 ,  Dan Chen  2 ,  Shengpeng Li  2 ,  Qingfeng Pang  2 ,  Zhiqiang Wang  1
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.
PMID: 33987410 DOI: 10.21037/atm-21-1448
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.
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