Abstract
In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1β and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3-grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1β and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell-mediated severe immunopathology in helminthic disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Adhesion Molecules / biosynthesis
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / immunology*
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Cell Line
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Female
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Gene Silencing / immunology
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Granuloma / genetics
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Granuloma / immunology
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Granuloma / pathology
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Interleukin-23 / genetics
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Interleukin-23 / immunology
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Interleukin-23 / metabolism
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Lectins, C-Type / biosynthesis
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology*
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / immunology
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Mice
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Mice, Inbred CBA
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / immunology
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Proto-Oncogene Proteins c-raf / metabolism
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Proto-Oncogene Proteins pp60(c-src) / genetics
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Proto-Oncogene Proteins pp60(c-src) / immunology
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Receptors, Cell Surface / biosynthesis
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology*
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Schistosoma / genetics
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Schistosoma / immunology*
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Schistosoma / metabolism
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Schistosomiasis / genetics
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Schistosomiasis / immunology*
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Schistosomiasis / metabolism
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Schistosomiasis / pathology
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Spleen / immunology
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Spleen / metabolism
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Spleen / pathology
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Th17 Cells / pathology
Substances
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Cell Adhesion Molecules
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DC-specific ICAM-3 grabbing nonintegrin
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Interleukin-1beta
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Interleukin-23
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Lectins, C-Type
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Receptors, Cell Surface
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Proto-Oncogene Proteins pp60(c-src)
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 3