A Novel Bifunctional Fusion Protein (Anti-IL-17A-sST2) Protects against Acute Liver Failure, Modulating the TLR4/MyD88 Pathway and NLRP3 Inflammasome Activation

• Published in: Biomedicines 2024-05, Vol.12 (5), p.1118
• Main Authors: Bai, Yu, Zhou, Rongrui, Xie, Xinlei, Zhu, An, Nan, Yanyang, Wu, Tao, Hu, Xiaozhi, Cao, Zhonglian, Ju, Dianwen, Fan, Jiajun
• Format: Article
• Language: English
• Subjects: acute liver failure; Antibodies; Biological activity; Biotechnology; Caspase-1; Chemokines; Chromatography; Cytokines; Dendritic cells; Development and progression; Drug dosages; Fusion protein; Health aspects; IL-17A; IL-33/ST2; Inflammasomes; Inflammation; Inflammatory diseases; Investigations; Leukocytes (neutrophilic); Lipopolysaccharides; Liver; Liver failure; Liver transplants; LPS/D-GalN; Lymphocytes T; Macrophages; MyD88 protein; NLRP3; Pathogenesis; Proteins; Signal transduction; Spleen; T cells; TLR4; TLR4 protein; Toll-like receptors; Tumor necrosis factor-α
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines12051118

Acute liver failure (ALF) is a serious inflammatory disorder with high mortality rates, which poses a significant threat to human health. The IL-33/ST2 signal is a crucial regulator in inflammation responses associated with lipopolysaccharide (LPS)-induced macrophages. The IL-17A signaling pathway promotes the release of chemokines and inflammatory cytokines, recruiting neutrophils and T cells under LPS stimulation, thus facilitating inflammatory responses. Here, the potential therapeutic benefits of neutralizing the IL-17A signal and modulating the IL-33/ST2 signal in ALF were investigated. A novel dual-functional fusion protein, anti-IL-17A-sST2, was constructed, which displayed high purity and biological activities. The administration of anti-IL-17A-sST2 resulted in significant anti-inflammatory benefits in ALF mice, amelioration of hepatocyte necrosis and interstitial congestion, and reduction in TNF-α and IL-6. Furthermore, anti-IL-17A-sST2 injection downregulated the expression of TLR4 and NLRP3 as well as important molecules such as MyD88, caspase-1, and IL-1β. The results suggest that anti-IL-17A-sST2 reduced the secretion of inflammatory factors, attenuated the inflammatory response, and protected hepatic function by regulating the TLR4/MyD88 pathway and inhibiting the NLRP3 inflammasome, providing a new therapeutic approach for ALF.