The Sweet-Side of Leukocytes: Galectins as Master Regulators of Neutrophil Function

Abstract

Among responders to microbial invasion, neutrophils represent one of the earliest and perhaps most important factors that contribute to initial host defense. Effective neutrophil immunity requires their rapid mobilization to the site of infection, which requires efficient extravasation, activation, chemotaxis, phagocytosis, and eventual killing of potential microbial pathogens. Following pathogen elimination, neutrophils must be eliminated to prevent additional host injury and subsequent exacerbation of the inflammatory response. Galectins, expressed in nearly every tissue and regulated by unique sensitivity to oxidative and proteolytic inactivation, appear to influence nearly every aspect of neutrophil function. In this review, we will examine the impact of galectins on neutrophils, with a particular focus on the unique biochemical traits that allow galectin family members to spatially and temporally regulate neutrophil function.

Keywords: galectin; glycans; glycoscience; inflammation; neutrophil.

Figure 1

The galectin family. Galectins are divided into prototypical, chimeric, and tandem repeat subfamilies. Representative members of each family are shown.

Figure 2

Example of galectin signaling in neutrophils. Galectin engagement of glycoconjugates on the cell surface can result in signaling events that alter neutrophil function. This schematic highlights potential signaling pathways engaged following galectin-1 binding that may result in phosphatidylserine (PS) exposure and subsequent neutrophil removal.

Figure 3

Regulation of galectin activity. Several galectins require reduced thiol groups to maintain carbohydrate recognition activity. Formation of intra- and inter-molecular disulfide bridges can result in significant conformational changes the preclude carbohydrate recognition. As monomers appear to be a key intermediate in oxidative inactivation and carbohydrates can drive dimerization, ligand appears to reduce oxidative inactivation by facilitating dimer formation (${\text{K}}_{\text{d}}^1$ < ${\text{K}}_{\text{d}}^2$). [hi] = higher concentrations of galectin-1 (Gal-1). [low] = lower concentrations of Gal-1. In contrast, several galectins, especially tandem repeat and chimeric galectins, rely on linker peptide bound carbohydrate recognition domains or N terminal collagen-like domains to facilitate dimerization. Cleavage of intervening peptides that connect oligomerization domains to functional carbohydrate recognition domains can render carbohydrate recognition domains monomeric and therefore incapable of generating signaling lattices typically thought to be required for optimal galectin-mediated signaling.

Figure 4

Galectins regulate a broad range of neutrophil activities. Different galectin family members influence various stages of neutrophil biology, ranging from extravasation, activation and chemotaxis to eventual turnover. Some galectins have been reported to have opposite activities on neutrophils that may reflect different types of inflammation.

Figure 5

Galectin regulation of neutrophil turnover. As the intracellular environment is reducing, intracellular stores of galectin remain active. However, following cellular injury, intracellular galectin becomes exposed to the extracellular oxidizing environment, where galectin oxidation and inactivation may occur. Rapid infiltration of neutrophils following injury allows for neutralization of potential pathogens and removal of necrotic tissue. As most extracellular galectin may become oxidized following injury prior to significant neutrophil recruitment, the ability of galectins to induce neutrophil turnover would be compromised, preventing galectins from inhibiting a productive inflammatory response. Following removal of necrotic tissue and pathogens, neutrophil encroachment on surrounding viable tissue results in cellular damage and release of reduced and therefore active galectin. Released galectins then engage neutrophils impinging on surrounding viable tissue, induce an oxidative burst that facilitates killing of ingested pathogens and the induction of PS exposure. As galectin-induced PS exposure occurs in the absence of apoptosis, this allows neutrophils to maintain membrane integrity in an otherwise inflammatory environment until successfully phagocytosed by monocyte-differentiated macrophages, which are typically outnumbered by neutrophils and are recruited after significant neutrophil influx. Once neutrophils are removed and inflammation subsides, tissue repair and regeneration ensue.