Structural and functional diversity of neutrophil glycosylation in innate immunity and related disorders

The granulated neutrophils are abundant innate immune cells that utilize bioactive glycoproteins packed in cytosolic granules to fight pathogenic infections, but the neutrophil glycobiology remains poorly understood. Facilitated by technological advances in glycoimmunology, systems glycobiology and glycoanalytics, a considerable body of literature reporting on novel aspects of neutrophil glycosylation has accumulated. Herein, we summarize the building knowledge of the structural and functional diversity displayed by N- and O-linked glycoproteins spatiotemporally expressed and sequentially brought-into-action across the diverse neutrophil life stages during bone marrow maturation, movements to, from and within the blood circulation and microbicidal processes at the inflammatory sites in peripheral tissues. It transpires that neutrophils abundantly decorate their granule glycoproteins including neutrophil elastase, myeloperoxidase and cathepsin G with peculiar glyco-signatures not commonly reported in other areas of human glycobiology such as hyper-truncated chitobiose core- and paucimannosidic-type N-glycans and monoantennary complex-type N-glycans. Sialyl Lewis^x, Lewis^x, poly-N-acetyllactosamine extensions and core 1-/2-type O-glycans are also common neutrophil glyco-signatures. Granule-specific glycosylation is another fascinating yet not fully understood feature of neutrophils. Recent literature suggests that unconventional biosynthetic pathways and functions underpin these prominent neutrophil-associated glyco-phenotypes. The impact of glycosylation on key neutrophil effector functions including extravasation, degranulation, phagocytosis and formation of neutrophil extracellular traps during normal physiological conditions and in innate immune-related diseases is discussed. We also highlight new technologies that are expected to further advance neutrophil glycobiology and briefly discuss the untapped diagnostic and therapeutic potential of neutrophil glycosylation that could open avenues to combat the increasingly prevalent innate immune disorders.