Abstract
Invasive candidiasis is a leading cause of nosocomial bloodstream infection. Neutrophils are the important effector cells in host resistance to candidiasis. To investigate the modulation of neutrophil fungicidal function will advance our knowledge on the control of candidiasis. While recombinant galectin-3 enhances neutrophil phagocytosis of Candida, we found that intracellular galectin-3 downregulates neutrophil fungicidal functions. Co-immunoprecipitation and immunofluorescence staining reveal that cytosolic gal3 physically interacts with Syk in neutrophils after Candida stimulation. Gal3−/− neutrophils have higher level of Syk activation as well as greater abilities to generate reactive oxygen species (ROS) and kill Candida than gal3+/+ cells. While galectin-3 deficiency modulates neutrophil and macrophage activation and the recruitment of monocytes and dendritic cells, the deficiency does not affect the numbers of infiltrating neutrophils or macrophages. Galectin-3 deficiency ameliorates systemic candidiasis by reducing fungal burden, renal pathology, and mortality. Adoptive transfer experiments demonstrate that cell intrinsic galectin-3 negatively regulates neutrophil effector functions against candidiasis. Reducing galectin-3 expression or activity by siRNA or gal3 inhibitor TD139 enhances human neutrophil ROS production. Mice treated with TD139 have enhanced ability to clear the fungus. Our work unravels the mechanism by which galectin-3 regulates Syk-dependent neutrophil fungicidal functions and raises the possibility that blocking gal3 in neutrophils may be a promising therapeutic strategy for treating systemic candidiasis.
Highlights
Galectin-3 belongs to a family of evolutionarily highly conserved animal lectins
Previous studies revealed that recombinant gal3 positively regulates neutrophil functions when added exogenously, here we focused our study on the role of cell intrinsic gal3 in neutrophils
We show that gal3 serves as a negative regulator of human and mouse neutrophil anti-Candida functions
Summary
Galectin-3 (gal3) belongs to a family of evolutionarily highly conserved animal lectins It is structurally unique amongst all the known galectins by consisting of a proline- and glycine-rich non-lectin domain in the N-terminal part, in addition to the C-terminal carbohydrate-recognition domains (CRD) [1]. Gal binds to the N-acetyllactosamine motif of glycoproteins through its CRD and undergoes polymerization through its N-terminal part [1, 2]. It is expressed in macrophages, Gal Regulates Neutrophil Function against Candida dendritic cells, activated lymphocytes, epithelial cells, and neutrophils and found in both intracellular and extracellular compartments as well as on the cell surface [3]. Point mutation at the CRD abolishes gal binding to Bax, thereby interfering its antiapoptotic effect [12], showing that the CRD of gal is involved in interaction with proteins, but the interaction is carbohydrate independent
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