Specific Recognition of Candida albicans by Macrophages Requires Galectin-3 to Discriminate Saccharomyces cerevisiae and Needs Association with TLR2 for Signaling

Abstract

Stimulation of cells of the macrophage lineage is a crucial step in the sensing of yeasts by the immune system. Glycans present in both Candida albicans and Saccharomyces cerevisiae cell walls have been shown to act as ligands for different receptors leading to different stimulating pathways, some of which need receptor co-involvement. However, among these ligand-receptor couples, none has been shown to discriminate the pathogenic yeast C. albicans. We explored the role of galectin-3, which binds C. albicans β-1,2 mannosides. These glycans are specifically and prominently expressed at the surface of C. albicans but not on S. cerevisiae. Using a mouse cell line and galectin-3-deleted cells from knockout mice, we demonstrated a specific enhancement of the cellular response to C. albicans compared with S. cerevisiae, which depended on galectin-3 expression. However, galectin-3 was not required for recognition and endocytosis of yeasts. In contrast, using PMA-induced differentiated THP-1, we observed that the presence of TLR2 was required for efficient uptake and endocytosis of both C. albicans and S. cerevisiae. TLR2 and galectin-3, which are expressed at the level of phagosomes containing C. albicans, were shown to be associated in differentiated macrophages after incubation with this sole species. These data suggest that macrophages differently sense C. albicans and S. cerevisiae through a mechanism involving TLR2 and galectin-3, which probably associate for binding of ligands expressing β-1,2 mannosides specific to the C. albicans cell wall surface.

Lack of galectin‐3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection

“…Indeed other lectins have been shown to cooperate with TLR-driven pathways, culminating in enhanced cytokine production [39,40]. Recently, galectin-3 was found to be coprecipitated with TLR2 in THP-1 cells after incubation with C. albicans blastoconidia, suggesting that galectin-3 may be associated with TLR2 at the membrane and following interaction with the yeast [21]. However, it was also shown that gal3 À/À macrophages produced lower amounts of TNF-a after incubation with C. albicans, compared with gal3 1/1 macrophages.…”

“…Recently, galectin-3 and TLR2 have been found to be associated in C. albicans-infected differentiated macrophages, an association that has been considered essential for TLR2-dependent cytokine production in response to the fungal infection [21]. Therefore, galectin-3 has been considered as a novel pattern recognition receptor, acting either alone or in concert with Toll-like receptors (TLR).…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…134 Galectin-3 on the surface of murine macrophages specifically recognizes C. albicans, which needs the association of TLR2 for signaling. 108 Interestingly, Galectin-3 also works in association with Dectin-1 on macrophages. 135 When macrophages expressing Dectin-1 are exposed to C. albicans mutants with increased exposure of b-glucan, the loss of Galectin-3 dramatically accentuates the failure to trigger an appropriate TNF-a response.…”

“…23 Galectin-3 on the surface of murine macrophages can bind to the b-1,2 mannosides of C. albicans. 107,108 In human neutrophil, Galectin-3 plays an important role in phagocytosing C. albicans hyphae, but not C. albicans yeasts. 109 Dectin-2 is another PRR for phagocytic cells to recognize C. albicans mannans.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…Gal-3 has been shown to interact with dectin-1 and TLR-2. 77,78 Previous studies using knockout mice have demonstrated that TGF-b1 and IL-6 fuel Th17 differentiation, while IL-23 facilitates the differentiation and sustains the Th17 cells. [79][80][81] IL-17A acts on a variety of cell types to promote inflammation 82 and helps eradicate extracellular pathogens.…”