Baicalin Inhibits Influenza A Virus Infection via Promotion of M1 Macrophage Polarization.

Ping Geng,Chenggang Huang,Xunlong Shi,Yiou Cao,Chang Su,Wei Zhou,Chengjie Xia,Hai Huang,Mingcang Chen,Haiyan Zhu

doi:10.3389/fphar.2020.01298

Abstract

Background and AimsThe natural compound baicalin (BA) possesses potent antiviral properties against the influenza virus. However, the underlying molecular mechanisms of this antiviral activity and whether macrophages are involved remain unclear. In this study, we, therefore, investigated the effect of BA on macrophages.MethodsWe studied macrophage recruitment, functional phenotypes (M1/M2), and the cellular metabolism via flow cytometry, qRT-PCR, immunofluorescence, a cell culture transwell system, and GC-MS–based metabolomics both in vivo in H1N1 A virus-infected mice and in vitro.ResultsBA treatment drastically reduced macrophage recruitment (CD11b+, F4/80+) by approximately 90% while maintaining the proportion of M1-polarized macrophages in the bronchoalveolar lavage fluid of infected mice. This BA-stimulated macrophage M1 phenotype shift was further verified in vitro in ANA-1 and primary peritoneal macrophages by measuring macrophage M1 polarization signals (CD86, iNOS, TNF-α, iNOS/Arg-1 ratio, and IL-1β cleavage). Meanwhile, we observed an activation of the IFN pathway (upregulation of IFN-β and IRF-3), an inhibition of influenza virus replication (as measured by the M gene), and distinct cellular metabolic responses in BA-treated cells.ConclusionBA triggered macrophage M1 polarization, IFN activation, and other cellular reactions, which are beneficial for inhibition of H1N1 A virus infection.

Highlights

Influenza viruses are the most frequent human pathogens and are responsible for many complications, such as viral pneumonia (Rello, 2017; http://www.who.int/influenza/surveillance_ monitoring/updates/latest_update_GIP_surveillance/en/)
We found that BA could inhibit influenza virus–induced autophagy in macrophages (Zhu et al, 2015)
We collected the bronchoalveolar lavage fluid (BALF) of infected mice at 4 days postinfection and analyzed macrophage recruitment and phenotype

Summary

Introduction

Influenza viruses are the most frequent human pathogens and are responsible for many complications, such as viral pneumonia (Rello, 2017; http://www.who.int/influenza/surveillance_ monitoring/updates/latest_update_GIP_surveillance/en/). Macrophages are one of the primary sources of inflammatory cytokines (such as TNF-a/chemokines) and act as critical modulators of influenza virus infection severity and the development of lethal pulmonary injury (Cardani et al, 2017). Their phenotype—classically activated (M1) or alternatively activated (M2)—is recognized as a key regulating factor in the initiation, progression, and termination of numerous inflammatory diseases (Li et al, 2018), in particular in influenza diseases (Arora et al, 2018). Modulating macrophage polarization might represent a possible therapeutic strategy for influenza virus infection (Vergadi et al, 2017; Halstead et al, 2018). We, investigated the effect of BA on macrophages

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