Galectin-3 negatively regulates dendritic cell production of IL-23/IL-17-axis cytokines in infection by Histoplasma capsulatum

• Published in: The Journal of immunology (1950) 2013-04, Vol.190 (7), p.3427-3437
• Main Authors: Wu, Sheng-Yang, Yu, Jhang-Sian, Liu, Fu-Tong, Miaw, Shi-Chuen, Wu-Hsieh, Betty A
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - immunology; Cytokines - biosynthesis; Dendritic Cells - immunology; Dendritic Cells - metabolism; Galectin 3 - genetics; Galectin 3 - metabolism; Histoplasma - immunology; Histoplasma capsulatum; Histoplasmosis - genetics; Histoplasmosis - immunology; Histoplasmosis - metabolism; Host-Pathogen Interactions - immunology; Interleukin-17 - biosynthesis; Interleukin-17 - pharmacology; Interleukin-23 - biosynthesis; Interleukin-23 - pharmacology; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Knockout; Neutrophils - immunology; Neutrophils - metabolism; Th17 Cells - cytology; Th17 Cells - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202122

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.