Elevated neuraminidase potentiates lung inflammation through facilitating integrin β2-mediated adhesion and immune responses of neutrophils.

Acute inflammation in the lungs is a leading cause of death worldwide, with limited treatments. During the development of inflammatory lung diseases, glycosylation is altered and emerges as a potential therapeutic target. Decreased sialylation is a common change in glycosylation. Yet the role of decreased sialylation in the progression of lung inflammation is complex and remains elusive. Here, we examined the role of sialic acids on neutrophils in modulating integrin β2-regulated cell adhesion and immune responses. The removal of sialic acids increased integrin β2-mediated adhesion and immune responses of neutrophils, including cytokine release, reactive oxygen species production, and neutrophil extracellular trap formation. In addition, the removal of sialic acids did not alter the ligand-binding affinity of integrin β2 but increased the ligand-binding valency of integrin β2. In inflamed lungs, the binding of the receptor for advanced glycation end product, a ligand highly expressed on lung epithelial cells, to integrin β2 facilitated the interaction of neutrophils with lung cells, which was also enhanced after removing sialic acids. Thus, sialic acids negatively regulate the valency of integrin β2 for its ligands and the subsequent neutrophil adhesion and ligand-induced immune responses. Our study suggests a mechanism by which decreased sialylation potentiates inflammation and provides novel insights into the pathogenesis of lung inflammation.