Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway
| Autor: | Zhi-Qi Gao, Dan Chen, Bin-bin Wan, Ya-Xian Wu, Shengpeng Li, Jiru Zhang, Si-Hao Jin, Zhiqiang Wang, Jiaojiao Sun, Gang Liu, Qing-feng Pang, Ying-ying Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
business.industry Inflammation General Medicine Lung injury Pharmacology respiratory system medicine.disease medicine.disease_cause In vitro Sepsis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system Staphylococcus aureus In vivo 030220 oncology & carcinogenesis medicine Original Article medicine.symptom business Oxidative stress |
| Zdroj: | Ann Transl Med |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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