5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo

Abstract

Influenza-related acute lung injury (ALI) is a life-threatening condition that results mostly from uncontrolled replication of influenza virus (IV) and severe proinflammatory responses. The methoxy flavonoid compound 5-methoxyflavone (5-MF) is believed to have superior biological activity in the treatment of cancer. However, the effects and underlying mechanism of 5-MF on IV-mediated ALI are still unclear. Here, we showed that 5-MF significantly improved the survival of mice with lethal IV infection and ameliorated IV-mediated lung edema, lung histological changes, and inflammatory cell lung recruitment. We found that 5-MF has antiviral activity against influenza A virus (IAV), which was probably associated with increased expression of radical S-adenosyl methionine domain containing 2 (RSAD2) and suppression of endosomal acidification. Moreover, IV-infected A549 cells with 5-MF treatment markedly reduced proinflammatory mediator expression (IL-6, CXCL8, TNF-α, CXCL10, CCL2, CCL3, CCL4, GM-CSF, COX-2, and PGE2) and prevented P-IKBα, P-P65, and P-P38 activation. Interestingly, we demonstrated that 5-MF treatment could trigger activation of AMP-activated protein kinase (AMPK)α in IV-infected A549 cells, as evidenced by activation of the AMPKα downstream molecule P53. Importantly, the addition of AMPKα blocker compound C dramatically abolished 5-MF-mediated increased levels of RSAD2, the inhibitory effects on H1N1 virus-elicited endosomal acidification, and the suppression expression of proinflammatory mediators (IL-6, TNF-α, CXCL10, COX-2 and PGE2), as well as the inactivation of P-IKBα, P-P65, and P-P38 MAPK signaling pathways. Furthermore, inhibition of AMPKα abrogated the protective effects of 5-MF on H1N1 virus-mediated lung injury and excessive inflammation in vivo. Taken together, these results indicate that 5-MF alleviated IV-mediated ALI and suppressed excessive inflammatory responses through activation of AMPKα signaling.

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

“…Indeed, recent studies have demonstrated that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce the activation of p38/MAPK, resulting in an upregulation of proinflammatory cytokines and an enhanced replication of the virus ( Bouhaddou et al, 2020 ). It has been observed that inhibiting the p38/MAPK signaling pathway can effectively mitigate the Influenza virus (IV) replication and the excessive production of proinflammatory mediators ( Yang et al, 2022 ). Additionally, the infection of Newcastle Disease Virus (NDV) has been shown to induce the activation of p38/MAPK/Mnk1 signaling, facilitating the efficient synthesis of viral proteins ( Zhan et al, 2020 ).…”

UiO-66 nanoparticles combat influenza A virus in mice by activating the RIG-I-like receptor signaling pathway

“…IAV increased glycolysis to promote viral replication by inducing HIF-1 stabilization, transcription, translation, and activation [ 64 ]. MAPK and autophagy signaling pathways contributed to IAV virus-induced inflammation and lung injury [ 65 , 66 ]. FOXO signaling pathway has also been showed playing an important role in the IAV-induced alveolar macrophage dysfunction [ 67 ], and FoxO1 negatively regulated cellular antiviral response by promoting degradation of IRF3 [ 68 ].…”

Transcriptional Analysis of lncRNA and Target Genes Induced by Influenza A Virus Infection in MDCK Cells

“…Furthermore, these differential expression patterns were consistent with the RNA-seq results. Five of our screened DEGS have been reported to affect influenza virus replication in host cells: TLR2, IFIT5, and RSAD2 have been reported to inhibit replication, while HCLS1 and AP2B1 have been shown to promote replication [13][14][15][16][17]. The remaining 13 screened DEGs have also been shown to play an important role in a variety of viruses.…”

“…For example, the SARS-CoV-2 envelope (E) protein has been shown to specifically interact with the TLR2 receptor, which in turn plays its antiviral role by activating the NF-κB transcription factor and stimulating the production of the inflammatory chemokine CXCL8 [12]. In addition, some studies have shown that TLR2, IFIT5, RSAD2, CLDN1, and HCLS1 play an important role in regulating the replication of influenza and other viruses in host cells [13][14][15][16][17][18][19].…”