Hederasaponin C Alleviates Lipopolysaccharide-Induced Acute Lung Injury In Vivo and In Vitro Through the PIP2/NF-κB/NLRP3 Signaling Pathway

• Published in: Frontiers in immunology Vol. 13; p. 846384
• Main Authors: Han, Shan, Yuan, Renyikun, Cui, Yushun, He, Jia, Wang, Qin-Qin, Zhuo, Youqiong, Yang, Shilin, Gao, Hongwei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25.02.2022
• Subjects: acute lung injury; Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Acute Lung Injury - genetics; Adenosine Triphosphate; Animals; Epigenesis, Genetic; epigenetic; hederasaponin C; Immunology; Inflammasomes - metabolism; Inflammation Mediators - therapeutic use; Interleukin-6 - metabolism; Lipopolysaccharides - toxicity; Mice; NF-kappa B - metabolism; NF-κB; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; PIP2; Signal Transduction; Tumor Necrosis Factor-alpha - metabolism; NF-κB; hederasaponin C; NLRP3 inflammasome; epigenetic; acute lung injury; PIP2
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.846384

Gene transcription is governed by epigenetic regulation that is essential for the pro-inflammatory mediators surge following pathological triggers. Acute lung injury (ALI) is driven by pro-inflammatory cytokines produced by the innate immune system, which involves the nod-like receptor 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathways. These two pathways are interconnected and share a common inducer the phosphatidylinositol 4,5-bisphosphate (PIP2), an epigenetic regulator of (Ribosomal ribonucleic acid (rRNA) gene transcription, to regulate inflammation by the direct inhibition of NF-κB phosphorylation and NLRP3 inflammasome activation. Herein, we report that hederasaponin C (HSC) exerted a therapeutic effect against ALI through the regulation of the PIP2/NF-κB/NLRP3 signaling pathway. In lipopolysaccharide (LPS)/lipopolysaccharide + adenosine triphosphate (LPS+ATP)-stimulated macrophages, our results showed that HSC remarkably inhibited the secretion of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α). Moreover, HSC inhibited NF-κB/p65 nuclear translocation and the binding of PIP2 to transforming growth factor-β activated kinase 1 (TAK1). The intracellular calcium (Ca ) level was decreased by HSC the PIP2 signaling pathway, which subsequently inhibited the activation of NLRP3 inflammasome. HSC markedly alleviated LPS-induced ALI, restored lung function of mice, and rescued ALI-induced mice death. In addition, HSC significantly reduced the level of white blood cells (WBC), neutrophils, and lymphocytes, as well as pro-inflammatory mediators like IL-6, IL-1β, and TNF-α. Hematoxylin and eosin (H&E) staining results suggested HSC has a significant therapeutic effect on lung injury of mice. Interestingly, the PIP2/NF-κB/NLRP3 signaling pathway was further confirmed by the treatment of HSC with ALI, which is consistent with the treatment of HSC with LPS/LPS+ATP-stimulated macrophages. Overall, our findings revealed that HSC demonstrated significant anti-inflammatory activity through modulating the PIP2/NF-κB/NLRP3 axis and , suggesting that HSC is a potential therapeutic agent for the clinical treatment of ALI.