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Fisetin alleviates sepsis-induced multiple organ dysfunction in mice via inhibiting p38 MAPK/MK2 signaling

Authors: Hai-feng Zhang1, Hai-bo Zhang2, Xue-ping Wu1, Ya-ling Guo1, Wei-dong Cheng1, Feng Qian1,2,3
1 Department of Nephrology, First Affiliated Hospital of Bengbu Medical College, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu 233004, China
2 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
3 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, China
Correspondence to: Feng Qian: fengqian@sjtu.edu.cn,
DOI: 10.1038/s41401-020-0462-y
Received: 24 March 2020
Accepted: 11 June 2020
Advance online: 13 July 2020

Abstract

Sepsis-induced multiple organ dysfunction and inflammatory response are life-threatening symptoms without effective treatment. Fisetin, a dietary flavonoid extracted from berries and family Fabaceae, has displayed neuroprotective and anti-oxidant activities. In this study we investigated whether fisetin exerted a protective effect against sepsis-induced multiple organ dysfunction in mouse cecum ligation and puncture (CLP) model. The mice were injected with fisetin (10 mg/kg, ip) 0.5 h prior to CLP, and sacrificed 18 h after CLP. We found that fisetin administration significantly alleviated CLP-induced lung, liver and kidney injury, as well as the expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β in bronchoalveolar lavage fluid (BALF). In lipopolysaccharide (LPS)-treated mouse bone marrow-derived macrophages (BMDMs), application of fisetin (3–10 μM) dose- dependently inhibited the expression levels of IL-6, TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS). Furthermore, fisetin dose-dependently inhibited the phosphorylation of p38 MAPK, MK2, and transforming growth factor-β-activated kinase (TAK) 1 via attenuating the interaction between TAK1 and TAK-binding proteins (TAB) 1. These results demonstrate that fisetin is a promising agent for protecting against sepsis-induced inflammatory response and organ injury via inhibiting macrophage activation.
Keywords: Fisetin; sepsis; multiple organ dysfunction; inflammation; mouse cecum ligation and puncture (CLP) model; macrophages

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