IL-10 dampens TNF/inducible nitric oxide synthase-producing dendritic cell-mediated pathogenicity during parasitic infection.

Antiparasite responses are associated with the recruitment of monocytes that differentiate to macrophages and dendritic cells at the site of infection. Although classically activated monocytic cells are assumed to be the major source of TNF and NO during Trypanosoma brucei brucei infection, their cellular origin remains unclear. In this study, we show that bone marrow-derived monocytes accumulate and differentiate to TNF/inducible NO synthase-producing dendritic cells (TIP-DCs) in the spleen, liver, and lymph nodes of T. brucei brucei-infected mice. Althouth TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogen, we report that TIP-DCs, as a major source of TNF and NO in inflamed organs, could contribute actively to tissue damage during the chronic stage of T. brucei brucei infection. In addition, the absence of IL-10 leads to enhanced differentiation of monocytes to TIP-DCs, resulting in exacerbated pathogenicity and early death of the host. Finally, we demonstrate that sustained production of IL-10 following IL-10 gene delivery treatment with an adeno-associated viral vector to chronically infected mice limits the differentiation of monocytes tot TIP-DCs and protects the host from tissue damage.

Jaar van publicatie:2009

Trefwoorden:Genetic Vectors/administration & dosage, Genetic Vectors/immunology, Immunity, Cellular, Immunophenotyping, Interleukin-10/administration & dosage, Interleukin-10/deficiency, Interleukin-10/genetics, Interleukin-10/physiology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Monocytes/enzymology, Monocytes/immunology, Monocytes/metabolism, Monocytes/pathology, Nitric Oxide/antagonists & inhibitors, Nitric Oxide/biosynthesis, Nitric Oxide Synthase Type II/antagonists & inhibi, Nitric Oxide Synthase Type II/biosynthesis, Parasitemia/enzymology, Parasitemia/immunology, Parasitemia/pathology, Parasitemia/prevention & control, Trypanosoma brucei brucei/immunology, Trypanosoma brucei brucei/pathogenicity, Trypanosomiasis, African/enzymology, Trypanosomiasis, African/immunology, Trypanosomiasis, African/pathology, Trypanosomiasis, African/prevention & contro, Tumor Necrosis Factor-alpha/antagonists & inhibito, Tumor Necrosis Factor-alpha/biosynthesis, Cell Differentiation/immunology, Cell Line, Dendritic Cells/enzymology