Article

β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling

Authors: Bei-xian Zhou1, Jing Li2, Xiao-li Liang2, Xi-ping Pan3, Yan-bing Hao2, Pei-fang Xie2, Hai-ming Jiang2, Zi-feng Yang2,4,5, Nan-shan Zhong2,4
1 Department of Pharmacy, The People’s Hospital of Gaozhou, Gaozhou 525200, China
2 State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
3 Institute of Combination Chinese and Western Medicine, Guangzhou Medical University, Guangzhou 511436, China
4 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, SAR, China
5 KingMed Virology Diagnostic & Translational Center, Guangzhou 510320, China
Correspondence to: Zi-feng Yang: Jeffyah@163.com, Nan-shan Zhong: nanshan@vip.163.com,
DOI: 10.1038/s41401-020-0403-9
Received: 20 September 2019
Accepted: 17 March 2020
Advance online: 5 June 2020

Abstract

β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150–450 μg/mL) dose- dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid- inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon- stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN- sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg−1·d−1, i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.
Keywords: influenza A virus; β-sitosterol; RIG-I; IFN-β; anti-inflammatory; acute lung injury

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