Total Flavonoids of Lophatherum gracile Alleviate Pseudorabies Virus Induced Inflammation by Modulating NF-κB/MAPK Signaling and TCA Cycle-Related Metabolism

Pseudorabies virus (PRV) infection induces severe inflammatory injury and tissue damage.Total flavonoids of Lophatherum gracile (TFLG) exert excellent antiinflammation effects, it alleviates the inflammatory damage caused by PRV infection remains unclear.Here, RAW264.7 cells and mouse models were used to evaluate the protective effects of TFLG on PRV-induced inflammatory injury and to clarify its underlying mechanism.Results showed that TFLG had no cytotoxicity at 0.025-0.1mg/mLand significantly improved the viability of PRV-infected cells.In PRV-infected mice, TFLG reduced abnormal increases in inflammatory cells and improved organ indices and histopathological injury.In RAW264.7 cells and mice, TFLG markedly reduced NO release and inhibited the production and mRNA levels of IL-1β, IL-6 and TNF-α.Meanwhile, TFLG increased IL-10 expression.Moreover, TFLG restrained PRV-mediated NF-κB/MAPK pathways activation, accompanied by reduced phosphorylation of p65, IκBα, p38 and JNK.Untargeted metabolomics further revealed that PRV caused marked metabolic disorders in cells and mouse serum, whereas TFLG partially recovered these metabolic changes.TCA cycle was a common metabolic pathway involved in the protective effect of TFLG.The correlation analyses suggested that TFLG may attenuate inflammation by regulating glutamine/glutamate-derived α-ketoglutarate metabolism, thereby relieving the inflammatory activation mediated by NF-κB/MAPK signaling pathway.This study provides new evidence that TFLG alleviates PRV-induced inflammatory injury through regulating metabolic-immune axis, which will contribute to TFLG as a promising natural candidate for the prevention and control of virus-associated inflammatory damage.