Trefoil factor 2 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 infection remains elusive. Here, we demonstrate that TFF2 protects mice against pneumonia in influenza virus infections. <i>In vitro</i> studies have revealed that TFF2 does not directly bind to the previously reported potential receptors but 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 relies on the TFF2-A4GNT-glycan axis during influenza virus infection. In the future, TFF2 may offer a potential intervention strategy for acute respiratory inflammatory diseases.