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. Although TIP-DCs have been shown to play a beneficial role in the elimination of several intracellular pathogens, 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 to TIP-DCs and protects the host from tissue damage.
Guilliams
Martin
M
Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium.
Movahedi
Kiavash
K
Bosschaerts
Tom
T
VandenDriessche
Thierry
T
Chuah
Marinee Khim
MK
Hérin
Michel
M
Acosta-Sanchez
Abel
A
Ma
Ling
L
Moser
Muriel
M
Van Ginderachter
Jo A
JA
Brys
Lea
L
De Baetselier
Patrick
P
Beschin
Alain
A
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007111:Immunity, Cellular; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018512:Parasitemia / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014346:Trypanosoma brucei brucei / Q000276:immunology* / Q000472:pathogenicity*; D014353:Trypanosomiasis, African / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II