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Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE
Gang Liu1,2, Yaxian Wu2,3, Sihao Jin1,2
1Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China.
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.
Insights
4-octyl itaconate (4-OI) protects against acute lung injury caused by Methicillin-resistant Staphylococcus aureus (MRSA) by reducing inflammation. This compound activates the Nrf2 pathway, offering a potential therapeutic strategy for MRSA-induced sepsis and lung damage.
Area of Science:
- Biomedical Science
- Inflammation Research
- Pulmonary Medicine
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of sepsis.
- Itaconate, a metabolite, possesses anti-inflammatory properties.
- Acute lung injury (ALI) is a severe complication of MRSA infections.
Purpose of the Study:
- To investigate the protective effects of 4-octyl itaconate (4-OI) against MRSA-induced ALI.
- To elucidate the underlying molecular mechanisms of 4-OI's anti-inflammatory action.
Main Methods:
- MRSA-induced ALI mouse model.
- Histopathological analysis (HE staining, immunohistochemistry).
- Western blot (WB) and quantitative PCR (qPCR) for inflammatory markers.
- Molecular docking to assess 4-OI-Keap1 interaction.
- Nrf2 inhibition studies (ML385 and Nrf2 knockout mice).
Main Results:
- 4-OI treatment improved survival rates and reduced lung pathology in MRSA-infected mice.
- 4-OI significantly inhibited neutrophil infiltration and bacterial load in the lungs.
- 4-OI suppressed inflammatory factors by activating the Nrf2 pathway, both in vivo and in vitro.
- Molecular docking confirmed stable binding of 4-OI to Keap1.
- Nrf2 inhibition abrogated the protective effects of 4-OI.
Conclusions:
- 4-octyl itaconate (4-OI) demonstrates significant protective effects against MRSA-induced lung injury.
- The therapeutic action of 4-OI is mediated through the activation of the Nrf2/ARE signaling pathway.
- 4-OI represents a promising therapeutic agent for combating MRSA-related lung inflammation and sepsis.
