TFF2 Interacts with A4GNT to Regulate Inflammation to Protect against Pneumonia during Influenza Virus Infection

Trefoil factor 2 (TFF2) has been shown to reduce inflammation and promote mucosal repair in models of gastric and colonic injury. However, the role of TFF2 in acute respiratory tract virus infection remains elusive. Here, we demonstrate that TFF2 protects mice against pneumonia in influenza virus infections. In vitro studies have revealed that TFF2 recognizes the terminal GlcNAc-α-1,4-Gal disaccharide of cell surface proteins mediated by the glycosyltransferase activity of α1,4-N-acetylglucosaminyltransferase (A4GNT). Functionally, TFF2 organized membranous TFF2-A4GNT-glycan protein complex serves to restrain cellular inflammation pathways by augmenting inhibitory Tyr527 phosphorylation at the C-terminus of src-family kinases (SFKs), thereby effectively preventing the phosphorylation of stimulatory SFKs Tyr416. Finally, we have conclusively verified that the protective effect of TFF2 treatment relies on the TFF2-A4GNT-glycan axis during influenza virus infection. In the future, TFF2 may offer a new potential intervention strategy for inflammatory diseases induced by acute respiratory infections.三叶因子2（Trefoil factor 2, TFF2）已被证实可在胃与结肠损伤模型中减轻炎症反应并促进黏膜修复。然而，TFF2在急性呼吸道病毒感染中的作用仍不明确。本研究证实，TFF2可在流感病毒感染过程中保护小鼠免受肺炎侵袭。体外实验揭示，TFF2可识别由α1,4-N-乙酰葡糖胺转移酶（α1,4-N-acetylglucosaminyltransferase, A4GNT）的糖基转移酶活性介导的细胞表面蛋白末端GlcNAc-α-1,4-Gal二糖。功能层面上，膜结合型TFF2-A4GNT-聚糖蛋白复合物可通过增强Src家族激酶（SFKs）C端的抑制性Tyr527磷酸化，从而抑制细胞炎症通路，有效阻断激活型SFKs Tyr416位点的磷酸化。最后，本研究确证，在流感病毒感染期间，TFF2治疗的保护作用依赖于TFF2-A4GNT-聚糖轴。未来，TFF2或可为急性呼吸道感染诱导的炎症性疾病提供全新的潜在干预策略。