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.

• Authors: Sheng-Yang Wu, Jhang-Sian Yu, Fu-Tong Liu, Shi-Chuen Miaw, Betty A Wu-Hsieh
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 7 Pg. 3427-37 (Apr 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23455499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Galectin 3
• Interleukin-17
• Interleukin-23

Topics

• Animals
• Cell Differentiation (immunology)
• Cytokines (biosynthesis)
• Dendritic Cells (immunology, metabolism)
• Galectin 3 (genetics, metabolism)
• Histoplasma (immunology)
• Histoplasmosis (genetics, immunology, metabolism)
• Host-Pathogen Interactions (immunology)
• Interleukin-17 (biosynthesis, pharmacology)
• Interleukin-23 (biosynthesis, pharmacology)
• Macrophage Activation (immunology)
• Macrophages (immunology, microbiology)
• Mice
• Mice, Knockout
• Neutrophils (immunology, metabolism)
• Th17 Cells (cytology, immunology)