Galectin-3 Negatively Regulates Dendritic Cell Production of IL-23/IL-17–Axis Cytokines in Infection by Histoplasma capsulatum

Abstract

Galectin-3 (gal3) is known for its immunoregulatory functions in infectious, autoimmune, and inflammatory diseases. However, little is known about its regulatory role in the host's IL-17A response to infection. Using a mouse model of histoplasmosis in which both Th1 and Th17 responses contribute to fungal clearance, we investigated how gal3 regulates IL-17A responses. Our study showed that Histoplasma infection induced gal3−/− dendritic cells to produce significantly higher levels of IL-23, TGF-β1, and IL-1β than did gal3+/+ cells. Infected by the same inoculum of Histoplasma, gal3−/− mice had lower fungal burden and produced higher levels of IL-23/IL-17–axis cytokines and lower levels of IL-12 and IFN-γ. Additionally, there was an increase in Th17 cells and a reduction in Th1 cells in infected gal3−/− mice. In vitro Th1/Th17-skewing experiments excluded the intrinsic effect of gal3 on Th cell differentiation. Although neutrophils from both gal3+/+ and gal3−/− mice produced IL-17A upon IL-23 stimulation, their contribution to IL-17A production was greater in gal3−/− mice than in gal3+/+ mice. Compared with gal3+/+ dendritic cells, adoptive transfer of gal3−/− dendritic cells resulted in production of significantly higher levels of IL-17–axis cytokines and reduced fungal burden. It appears that reduced fungal burden and preferential IL-17A response in gal3−/− mice by both Th17 cells and neutrophils were the result of preferential production of IL-23/IL-17–axis cytokines by dendritic cells. Our study showed that gal3 negatively regulates IL-17A responses through inhibition of IL-23/IL-17–axis cytokine production by dendritic cells.

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…Using this concept, Wu et al demonstrated that gal-3 deficient mice cleared Histoplasma more efficiently than wild type mice, and that the DCs from the mutant mice produced higher levels of IL-23, TGF-b1, and IL-1b compared to the control mice. 85 H. capsulatum also induced higher levels of IL-17A and greater percentages of Th17 cells, but lower levels of IFN-g, IL-12 as well as a lower percentages of Th1 cells. The results of this study support the role of gal-3 in negatively regulating host IL-17 responses to Histoplasma by impeding IL-23/IL-17-axis cytokine production by DCs.…”

“…The results of this study support the role of gal-3 in negatively regulating host IL-17 responses to Histoplasma by impeding IL-23/IL-17-axis cytokine production by DCs. 85 Paracoccidioides brasiliensis Paracoccidioidomycosis (PCM) is caused by a complex group of fungi comprising 4 distinct phylogenetic lineages (PS2, PS3, S1 and Pb01-like). The first 3 lineages are speciated as Paracoccidioides brasiliensis whereas Pb01 is morphologically and genetically distinct and is designated as Paracoccidioides lutzii.…”

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…Reported data suggest that Galectin-3 suppresses IFN-γ production by antigen-specific CD8 + T cells in vitro (95). Further, dendritic cells lacking the Galectin-3 gene have been shown to increase both T-cell numbers and cytokine production in helminthic infections and promote an effective Th17 immune response (107,108). Altogether, it appears that Galectin-3 is involved in the tuning of acquired immunity against tumours by determining the cytokine milieu in the tumour microenvironment.…”

“…It has been suggested that Galectin-3 also influences the strength of antigen activation in dendritic cells (21,22) and controls acquired immunity, including both T-helper cell 1 (Th1) (23,24) and T-helper cell 2 (Th2) responses (21,25) depending on the context of the host immune response. Along with its role in inflammation and immune responses in noninfectious conditions, Galectin-3 can detect certain microorganisms by binding specific carbohydrate structures of glycoproteins and glycolipids from many pathogens (26).…”

The Cek1‑mediated MAP kinase pathway regulates exposure of α‑1,2 and β‑1,2‑mannosides in the cell wall ofCandida albicansmodulating immune recognition

“…This is potentially explained by the enhanced production of IL-23 cytokines observed in infected galectin-3 ¡/¡ dendritic cells. 90 A C. albicans strain defective in the b-1,2-mannosyltransferase Bmt1 and a strain with no b-M (bmt1 bmt2 bmt5 mutant) exhibit a similar or reduced virulence (respectively) in galectin-3 ¡/¡ mice compared to its wild type counterpart. 82 We demonstrate here that the avirulent phenotype of cek1 mutants 36 is not caused by the absence of galectin-3, despite the significant reorganization of the cell wall which is reflected in the epitopes that are recognized by this receptor in the surface of the cell.…”