title: Cell Intrinsic Galectin-3 Attenuates Neutrophil ROS-Dependent Killing ofCandidaby Modulating CR3 Downstream Syk Activation.
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 ofCandida, 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 afterCandidastimulation.Gal3-/-neutrophils have higher level of Syk activation as well as greater abilities to generate reactive oxygen species (ROS) and killCandidathangal3+/+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.
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine , Taipei , Taiwan.
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine , Taipei , Taiwan.
authors.forename: Juin-Hua
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine , Taipei , Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei , Taiwan.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chan
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei , Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital , Taipei , Taiwan.
authors.forename: Yee-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei , Taiwan.
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Graduate Institute of Immunology, National Taiwan University College of Medicine , Taipei , Taiwan.
authors.forename: Betty A
authors.initials: BA
authors.lastname: Wu-Hsieh
keywords: Candida albicans; M2 macrophage; Syk kinase; TD139; galectin-3; monocyte/dendritic cell recruitment; neutrophil; reactive oxygen species